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  • 2000-2004  (140)
  • 1990-1994  (322)
  • 1890-1899
  • breast cancer
  • 101
    ISSN: 1573-7217
    Keywords: breast cancer ; microsatellite instability ; microsatellite markers ; review ; survey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Microsatellite markers may provide evidence of faulty DNA mismatch repair (MMR) via the detection of microsatellite instability (MSI). The choice of microsatellite markers may impact on the MSI detection rate. In hereditary non-polyposis colon cancer (HNPCC), several informative microsatellite markers have been recommended. Two of these, BAT 25 and BAT 26, are quasi-homozygous, enabling analysis of tumour DNA in the absence of paired normal DNA. Sixty-six breast cancer patients under 45 years of age at diagnosis were examined for MSI at BAT 25 and BAT 26. Tumour DNA was extracted from paraffin-embedded tissue. No MSI was detected at the BAT 25 or BAT 26 loci. An additional five microsatellite markers, known to be informative for HNPCC, were examined for MSI in these patients. Apparently-normal profiles were achieved. A tabulated survey of 306 microsatellite markers used to detect MSI in breast cancer revealed that only 35.5% of markers detected MSI at an average rate of 2.9%. The MSI detection rate at the specific HNPCC markers varied from 0% to 10% in breast cancer, with D175250 and TP53 being the HNPCC markers most suitable for analysis of breast cancer. The size of the microsatellite marker's repeat unit did not impact on MSI detection rates. Compiled data from large studies (n〉100) revealed D115988 as the marker with the highest MSI detection rate. Genomic instability pathways of carcinogenesis, characterised by MMR defects and MSI, appear to play a role in the genesis of some breast cancer types.
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  • 102
    ISSN: 1573-7217
    Keywords: aromatase inhibitor ; breast cancer ; liarozole ; retinoic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Liarozole is an imidazole compound that inhibits enzymes involved in steroid hormone aromatisation and retinoid metabolism. The IDBBC branch of the EORTC has performed a series of phase II studies of the agent in four groups of postmenopausal women with metastatic breast cancer. This paper reports the results of the first two groups: ‘Chemotherapy Resistant’ (unrestricted ER status, 1 or 2 prior chemotherapy regimens, 0–2 prior hormonal therapies) and ‘Potentially Hormone Sensitive’ (ER positive or unknown, 1 or 2 prior hormonal therapies with a substantial disease free interval or progression free survival, and no history of chemotherapy for metastatic disease). Liarozole was administered at 150–300 mg orally bid. The objective response rate was 12% in the ‘Chemotherapy Resistant’ group (n=34), and 22% in the ‘Potentially Hormone Sensitive’ group (n=37), with median response durations of 9 and 14 months, respectively. Median time to treatment failure was only 2 months in both groups, due largely to the significant percentage (24%) of patients who ceased treatment following excessive mucocutaneous and gastrointestinal toxicity. This adverse event profile will limit its use in breast cancer. Results of the ‘ER negative’ and ‘Tamoxifen Refractory’ groups will be reported in a future paper.
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  • 103
    ISSN: 1573-7217
    Keywords: active processed cathepsin D ; breast cancer ; prognostic indicator ; survival analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The relative amounts of the precursor (52 kDa) and processed (31,27 kDa) forms of cathepsin D have been analyzed by Western blotting in biopsied breast tissue cytosols from 134 lesions from invasive breast cancer patients, 24 lesions from patients with ductal carcinoma in situ (DCIS), 227 lesions from benign breast disease patients, and 28 lesions from normal control subjects. The mean relative percentage amount of the 31 kDa form was significantly increased (p〈0.001) in the invasive breast cancer group compared to the other three groups. In addition, the mean relative percentage amount of the 31 kDa form was significantly increased (p〈0.05) in node-positive compared to node-negative breast cancer patients. In the benign breast disease group, patients with proliferative-type disease had a significantly increased (p=0.02) mean relative percentage amount of the 31 kDa form of cathepsin D compared to patients with nonproliferative-type disease. Invasive breast cancer patients were followed for up to 75 months to determine if the relative percentage amount of the 31 kDa form of cathepsin D was predictive of disease-free and overall survival. Although the amount of the 31 kDa form was not predictive of disease-free survival, patients in the ‘high’ 31 kDa group (〉18) were significantly (p〈0.05) more likely to die than patients in the ‘low’ 31 kDa group (≤18%). The 12 patients who died were all node-positive and in the high 31 kDa group. It thus appears that the relative amount of the processed, active 31 kDa form of cathepsin D is a useful prognostic indicator, at least in node-positive breast cancer patients.
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  • 104
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 60 (2000), S. 259-266 
    ISSN: 1573-7217
    Keywords: TSG101 ; breast cancer ; tumor suppressor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Functional inactivation of the tsg101 gene in mouse fibroblasts results in cell transformation and the ability to form metastatic tumors in nude mice. The human tsg101 gene was mapped to chromosome 11q15.1-2 and found to mutate in some cancer patients. To test the expression pattern of the tsg101 gene in Chinese breast cancer patients, we analyzed the mRNA by RT-PCR in 51 breast cancer patients. The full-length tsg101 and 7 truncated transcripts were detected in both normal and matched tumor tissues. A short transcript with a deletion of nucleotides 154–1054 is frequently presented in late-stage breast cancers. TSG101 protein expression was also detected by Western blot analysis in 30 breast cancer patients. A predicted full-length 46 kDa and three proteins with smaller molecular weight were detected. The full-length 46 kDa protein was less expressed in tumor specimens. Immunohistochemical stains from 10 patients of each stage 0–4 revealed that TSG101 protein was predominantly present in the cytoplasm. Cell nuclei were occasionally immunopositive and the chromosomes were deeply stained during cell division. The intracellular location and the expression of TSG101 protein were both not stage-dependent in primary breast cancers. In addition, normal mammary glands were more homogenously immunopositive than invasive ductal carcinoma. These results support the notion that the aberrant expression of TSG101 in breast cancer is associated with altered cell growth.
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  • 105
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 60 (2000), S. 201-209 
    ISSN: 1573-7217
    Keywords: breast cancer ; growth rates ; histological grade ; primary medical treatment ; radiotherapy fractionation ; ‘split-course’ radiotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract ‘Timing’ of treatment in breast cancer may refer to intervals within a single management or between different managements. Rates of shrinkage of breast cancers in response to treatment are related to histological grade and may be used as surrogates for growth rates. Histological grade should predict appropriate timing of treatment. Four cases of locally advanced breast cancer that illustrate a number of different types of interval are presented. Two tumours of differing histological grade (II and III) had been managed by historical ‘split-course’ radiotherapy and two similar grade III tumours were managed by primary medical treatment, followed at different intervals by radiotherapy. In the grade III tumours different radiotherapy fractionation régimes and effects of varying intervals between mangements are compared. The theoretical advantage of shrinkage (leading to reoxygenation) during the gap in ‘split-course’ radiotherapy is realized only in relatively slowly growing and shrinking tumours. Grade III tumours grow rapidly. They have the potential to shrink rapidly in response to appropriate treatment, namely intensive chemotherapy or radiotherapy but not hormones. Inadequate treatment leads to growth in intervals between individual doses, whether of drugs or radiation, and to failure of local control. The advantage of surgery or primary medical treatment will be lost if the interval between managements is too long in relation to the volume doubling time. Histological grade is a good guide of this parameter; the grade III tumours are particularly vulnerable to gaps in treatment.
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  • 106
    ISSN: 1573-7217
    Keywords: breast cancer ; 5-fluorouracil ; methotrexate ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A novel approach is described to simulate effect site pharmacodynamics of anticancer drugs. This approach is based on (i) the in vivo measurement of unbound, interstitial drug pharmacokinetics (PK) in solid tumor lesions in patients and (ii) a subsequent pharmacodynamic (PD) simulation of the time versus drug concentration profile in an in vitro setting. For this purpose, breast cancer cells (MCF-7) were exposed in vitro to the time versus interstitial tumor concentration profiles of 5-fluorouracil (5-FU) and methotrexate (MTX) from primary breast cancer lesions in patients. This led to a maximal reduction in the viable cell count of 69 on day 4, and of 71 on day 7 for 5-FU and MTX, respectively. This effect was dependent on the initial cell count and was characterized by a high interindividual variability. For 5-FU there was a significant correlation between the maximum antitumor effect and the intratumoral AUC (r = 0.82, p = 0.0005), whereas no correlation could be shown for MTX (r = 0.05, p = 0.88). We conclude, that the in-vivo-PK / in-vitro-PD model presented in this study may provide a rational approach for describing and predicting pharmacodynamics of cytotoxic drugs at the target site. Data derived from this approach support the concept that tumor penetration of 5-FU may be a response-limiting event, while the response to MTX may be determined by events beyond interstitial fluid kinetics.
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  • 107
    ISSN: 1573-7217
    Keywords: breast cancer ; database ; prognosis ; Taiwan ; young age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Between April 1990 and December 1997, 811 consecutive patients with 830 newly diagnosed breast cancers having their primary treatments in our institution were included in this study. Sixty three percent of breast cancer patients were premenopausal. The early-onset breast cancer (age ≤ 40) composed 29.3% of all patients. The five-year survival rate of all patients was 80.4% (95% confidence interval [CI], 76.2–84.6%). The five-year overall survival rate for stage 0 was 95.7% (95% CI, 87.3–100%), stage I, 93.9% (95% CI, 88.9–98.9%), stage II, 88.5% (95% CI, 82.0–95.1%), stage III, 65.0% (95% CI, 54.0–75.9%), and stage IV, 18.5% (95% CI, 3.4–33.7%). Multivariate analysis of primary operable breast cancer revealed that axillary lymph node involvement, high nuclear grade and early-onset breast cancer (age ≤ 40) were poor prognostic factors. The early-onset breast cancer had a more aggressive clinical behavior than that of the older age group, their five-year disease-free survival rates for stage I, stage II and stage III diseases being only 64.7%, 66.5%, and 43.3%, respectively. In these patients the only meaningful prognostic factor was extensive axillary lymph node metastasis (≥10). In summary, breast cancer patients in Taiwan tend to be younger than their counterpart in western countries. The early-onset breast cancer had poorer prognostic features for all stages comparing to the older age group. Standard pathologic factors are not good predictors of their outcome. For these patients new biologic markers need to be sought to distinguish between high and low risk and the treatment strategy for them should be guided by the aggressive characteristics of the disease.
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  • 108
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 63 (2000), S. 225-234 
    ISSN: 1573-7217
    Keywords: breast cancer ; cholesterol ; triglycerides ; tamoxifen ; toremifene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tamoxifen decreases serum cholesterol (S-cholesterol) level about 10% and low-density lipoprotein cholesterol (S-LDL) 15–20%, but in most studies it has increased serum triglyceride levels and had little effect on serum high-density cholesterol (S-HDL). The effect of another antiestrogen, toremifene, on the serum lipid profile has not been completely studied. We monitored serum lipid levels longitudinally in 141 axillary node-positive postmenopausal breast cancer patients who received randomly either 40 mg toremifene or 20 mg tamoxifen as adjuvant therapy for 36 months, and in 34 postmenopausal women who received no adjuvant systemic therapy after surgery for axillary node-negative breast cancer. No significant differences were found between the drugs in their effects on S-cholesterol, LDL, HDL, or triglyceride levels, or on the cholesterol-to-HDL or LDL-to-HDL ratios. For both drugs the S-cholesterol and S-LDL absolute lowering effect was the greater the higher the pretreatment level. For a patient with a median pretreatment value, toremifene decreased S-cholesterol 6% and tamoxifen 13%, and S-LDL decreased by 13% and 23%, respectively, at 6 months of therapy. Six months after stopping three-year antiestrogen therapy S- cholesterol and S-LDL levels had returned to the pretreatment levels. In conclusion, we found no major differences between 40 mg toremifene and 20 mg of tamoxifen in their effect on the serum lipid levels, which return to the pretreatment levels within 6 months after cessation of therapy.
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  • 109
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 64 (2000), S. 201-209 
    ISSN: 1573-7217
    Keywords: alcohol ; breast cancer ; cohort ; women
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Available epidemiological evidence indicates that alcohol intake is associated with a higher risk of developing breast cancer. Plausible biological pathways include its effect on levels of estrogens, cell membrane integrity and cell-to-cell communication, inhibition of DNA repair, and congener effect. The present study evaluated the impact of alcohol on mortality from breast cancer, an area with relatively few studies in the literature. The subjects were participants in a Canadian prospective cohort study, the National Breast Screening Study (NBSS). Women were enrolled in the cohort from 1980 to 1985 to evaluate the efficacy of mammographic screening. Information on usual diet and alcohol intake at enrolment and other epidemiological variables was collected by means of a mailed, self-administered questionnaire. Mortality from breast cancer during follow- up to 31 December, 1993 was ascertained by record linkage to the Canadian Mortality Data Base maintained by Statistics Canada. During the follow-up period of 1980–1993 (average 10.3 years), 223 deaths from breast cancer were identified for this analysis. The hazard ratios for the risk of death from breast cancer increased with intakes of total alcohol of 10–20 g/day (1.039, 1.009–1.071) and 〉 20 g/day (1.063, 1.029–1.098). This increase was contributed largely by the intake of wine, a 15% increase in risk at intakes higher than 10 g/day of alcohol from wine. Alcohol from spirits was associated with a small decrease in risk of death (hazard ratio at 10 g/day, 0.945, 0.915–0.976). The effect of alcohol from beer was not significant in the two categories studied. Although our results were statistically significant, the magnitude of the change in risk was small.
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  • 110
    ISSN: 1573-7217
    Keywords: breast cancer ; EGF receptor ; erbB2 ; estrogen receptor ; LAR ; 13762NF tumor ; tyrosine phosphatase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Several prognostic indices in breast cancer, including c-erbB2, epithelial growth factor receptors (EGFR), estrogen and progesterone receptors are signal transduction molecules. Recently, expression of another signal transduction molecule, the protein tyrosine phosphatase LAR, has been suggested to be increased in breast cancer. The objective of the current investigation was to examine the relationship between LAR expression and prognostic parameters in breast cancer. LAR expression was associated with metastatic potential in the well-characterized 13762NF rat mammary adenocarcinoma clones. The metastatic MTLn3 and MTLn2 clones expressed sizable amounts of LAR. The essentially non-metastatic MTC clone had little LAR expression. C-erbB2 had highest expression in the highly metastatic MTLn3 clone, but c-erbB2 levels were sizeable in the weakly metastatic MTLn2 and non-metastatic MTC clone. EGFR expression had the strongest association with a clone's metastatic potential, being very high in MTLn3, weak in MTLn2, and undetectable in MTC. In human breast cancer specimens, LAR expression was strongly positive in 50% of metastatic cases but in only 21% of ‘non-metastatic’ cases. As with the 13762NF-derived clones, c-erbB2 expression was strongly positive independent of metastatic phenotype. However, 46% (6/13) of cases that were strongly positive for c-erbB2 were strongly positive for LAR. Only 17% (2/11) of negative or weakly c-erbB2 positive samples were strongly positive for LAR. All ER+ positive tumors (n = 15) were positive for LAR and 53% of these tumors were strongly positive for LAR. In ER− negative cases, only 1 of 11 was strongly positive for LAR. While the current data indicate a strong association between ER and LAR expression in breast cancer tissue (p = 0.003), additional studies are warranted to further explore the relationship between LAR and prognostic indices of breast cancer progression.
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  • 111
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 61 (2000), S. 33-43 
    ISSN: 1573-7217
    Keywords: breast cancer ; p21WAF1/CIP1 ; p53 ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract p21WAF1/CIP1 is transcriptionally activated by wt p53 and inhibits G1 associated cyclins, a major mechanism by which p53 inhibits cellular proliferation. Archival breast cancers (798) with a median follow-up of 16.3 years were used to explore the prognostic value of p2l immunohistochemical analyses. p21 immunostaining was detected in the majority (726/798: 91%) of breast cancers as well as adjacent in situ carcinomas (125/170: 74%), hyperplastic lesions (140/349: 40%) and normal breast epithelium adjacent to carcinoma (3/89: 3%). Complete immunonegativity was observed in only 9% of invasive cancers and was associated with p53 immunopositivity (p〈0.05). Univariate analysis of all patients showed that p21 negativity was associated with a longer disease specific survival (relative risk (RR) 1.5). Node positive p21 – patients also showed a longer disease free and disease specific survival as compared to tumor p21+ patients. In node negative patients, p53 positivity but not p21 alone, was significantly associated with a shortened disease free survival (RR = 1.6). Node negative patients who were p53 + p21−, in particular had the shortest disease free survival compared to other p53, p21 subgroups (i.e., p21 negativity was associated with a worse outcome). Multivariate analysis of lymph node negative patients (n〉300) demonstrated that tumor size and tumor grade were independently predictive of outcome, whereas neither p53 nor p21 were significant. For node positive patients, p21 positivity (p=0.05), p53 positivity (p=0.03), a higher number of positive nodes, larger tumor size, steroid receptor negativity, high proliferation rate, and erbB-2 expression were each independently associated with poor outcome. In summary, p21 negativity was inversely correlated with p53 immunopositivity in the majority of cases. p21 negative tumor patients had an improved outcome if they were node positive, whereas p21 status was not significantly associated with survival in node negative patients. This observation may be due to the reported ‘uncoupling of S phase and mitosis’ associated with a loss of p21 expression which may result in enhanced sensitivity to chemotherapy.
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  • 112
    ISSN: 1573-7217
    Keywords: ataxia telangiectasia ; ATM ; breast cancer ; mutation screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Based upon the results of several epidemiologic studies, it has been suggested that women who are carriers for a mutation in the ataxia telangiectasia-mutated (ATM) gene are susceptible for the development of breast cancer. Therefore, 37 consecutive breast cancer patients were screened for the presence of a germline ATM mutation using a non-isotopic RNase cleavage-based assay (NIRCA). This paper reports the first use of NIRCA for detection of ATM mutations in breast cancer patients. Using this assay, no ATM mutations were found in our patient population. This result is similar to the findings of other studies that have employed approaches complementary to NIRCA.
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  • 113
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 61 (2000), S. 45-57 
    ISSN: 1573-7217
    Keywords: androgen receptor ; apoptosis ; Bax ; Bcl-2 ; breast cancer ; estrogen receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have established a Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis, in which the role of androgen in promoting mammary carcinogenesis was highlighted. We have also established that stromal-epithelial interactions may be responsible for the promotional effects of testosterone in mammary carcinogenesis. Based on these understandings, in the present study we examined the expression of Bcl-2 and Bax in pre-malignant mammary glands from rats treated with different protocols of sex hormones for 7 weeks as well as sex hormone induced mammary tumours. We observed that Bcl-2 was strongly expressed in most of mammary tumour cells, whereas weak or negative in adjacent normal or hyperplastic ductal structures. On the contrary, Bax immunoreactivity was weak in mammary tumour cells while strongly expressed in adjacent normal or hyperplastic ductal structures. More importantly, the results from comparative study of ‘pre-malignant’ glands further showed that when animals were treated with 17β-oestradiol, the mammary epithelial cells expressed high levels of Bcl-2. The results from rats treated with testosterone, either alone or in combination with oestrogen, give rise to high levels of Bax expression in ‘pre-malignant’ mammary glands. These observations indicate that in ‘pre-malignant’ mammary glands, treatment with testosterone, either alone or in combination with 17β-oestradiol, may induce high apoptotic activities. However, in fully developed mammary tumours, the apoptotic activities apparently decrease in tumour cells. TUNEL assay provides further data to support this conclusion. Our study, thus, suggests that androgens may play a promoting role in mammary carcinogenesis by upregulation of Bax expression and induction of high apoptotic activities in ‘pre-malignant’ stage, which would provide a selective pressure favouring the expansion of the initiated cells.
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  • 114
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 61 (2000), S. 121-129 
    ISSN: 1573-7217
    Keywords: breast cancer ; ex-smokers ; smoking ; smoking cessation ; tobacco
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract High plasma levels of oestrogens are associated with increased breast cancer risk. If smoking, as has been suggested, have both a tumour initiating mutagenic effect and a protective anti-oestrogenic effect, one would assume that smokers who give up smoking have the highest incidence of breast cancer. This was evaluated in the follow-up of a cohort of 10,902 women of whom 4,359 were premenopausal. Record-linkage with official cancer registries yielded 416 incident cases during an average follow-up of 13.6 years. The adjusted relative risk in all ex-smokers was 1.31 (1.02–1.69), as compared to never smokers, and in premenopausal ex-smokers it was 1.57 (1.07–2.30). Breast cancer incidence in premenopausal ex-smokers was inversely related to time since cessation, (p for trend = 0.01), and was highest among the women who had given-up smoking less than 12 months before screening: 2.76 (1.55–4.91). There was no significant association between current smoking and breast cancer risk. We conclude that incidence of breast cancer in premenopausal women who have given up smoking is higher than it is in smokers and never smokers. To what extent this may be related to endocrine effects associated with smoking cessation remains to be evaluated.
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  • 115
    ISSN: 1573-7217
    Keywords: breast cancer ; breast conserving surgery ; hospital practices ; mastectomy ; physician behavior
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We studied whether a hospital intervention utilizing medical opinion leaders and performance feedback reduced the proportion of women who reported that surgeons did not discuss options prior to surgery for early stage breast cancer. Opinion leaders provided clinical education to their peers using a variety of strategies and were selected for their ability to influence their peers. Performance feedback involved distributing performance reports that contained data on the outcomes of interest as well as on other treatment patterns. Twenty-eight hospitals in Minnesota were randomized to the intervention or to a control group that received performance feedback only. The proportion of patients at intervention hospitals who said that their surgeon did not discuss options decreased significantly (p〈0.001) from 33% to 17%, but a similar decrease was observed among control hospitals. Using medical opinion leaders to intervene in hospitals appeared as effective as performance feedback.
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  • 116
    ISSN: 1573-7217
    Keywords: androgen receptor ; breast cancer ; mutation ; polymorphism ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Prostate Specific Antigen (PSA) expression by breast epithelial cells is associated with favorable breast cancer prognosis. In preliminary studies, we found that a nucleotide variation (G → A) at position −158 in the androgen response element (ARE-1) of the PSA promoter was present in four out of 9 breast tumors examined and in a breast carcinoma cell line. We have now determined the nucleotide composition at position −158 of DNA extracted from 148 well-characterized breast tumors and compared tumor genotype with that of controls without cancer, with tumor PSA concentration and with clinicopathological variables, overall survival and disease free survival. The G → A base change at position −158 is a polymorphism. Allelotypes were similarly distributed in breast cancer patients and controls. The Mann–Whitney U Test showed a significantly higher tumor PSA concentration in tumors that presented a homozygous G as opposed to homozygous A genotype. Genotype at position −158 was not associated with clinicopathological variables in contingency table analysis. Univariate Cox regression models showed a 28% reduction in risk for death in patients with homozygous G genotype compared to those with homozygous A genotype (P=0.03). However, ARE-I genotype did not significantly add to the prognostic power in the multivariate model of overall survival. In summary, the base change at position −158 is a polymorphism that may affect breast cancer prognosis, but further studies are required to confirm this possibility and to investigate the relevance of this polymorphism in terms of breast cancer susceptibility.
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  • 117
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    Springer
    Breast cancer research and treatment 61 (2000), S. 139-143 
    ISSN: 1573-7217
    Keywords: breast cancer ; mutation ; nipple aspirate fluid ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Nipple Aspirate Fluid (NAF) from patients with breast cancer is a potential source of exfoliated tumour material amenable to molecular biological study, but few such data have been reported. In this study we demonstrate that polymerase chain reaction (PCR) amplification of p53 gene DNA is achievable in a proportion of NAF samples from breast cancer patients. Subsequently four NAF samples from patients whose primary tumours were identified as having a defined p53 mutation were studied by single stranded conformational polymorphism analysis (SSCP). Two samples yielded PCR product indistinguishable from wild type and two yielded no product. Whilst no cancer-related genetic mutations were demonstrated in NAF samples, further study is warranted.
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  • 118
    ISSN: 1573-7217
    Keywords: adjustment disorders ; breast cancer ; first recurrence ; major depressive disorder ; psychological distress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objectives: To investigate the prevalence of, and risk factors for psychological distress following first recurrences of breast cancer. Patients and methods: The sample was drawn consecutively from the inpatient and outpatient populations of the National Cancer Center Hospital in Japan during an 18-month period from July 1996 to December 1997. Of the 56 eligible patients, 55 women aged 30–73 year with recurrent breast cancer participated in the study. The prevalence of psychological distress, including major depressive disorder and adjustment disorders was evaluated according to the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Third edition-revised (DSM-III-R). Risk factors for psychological distress were analyzed with a logistic regression model. Results: Of the 55 subjects, 42 met the DSM-III-R criteria for major depressive disorder or adjustment disorders. Major depressive disorder was seen in 4 (7%), and adjustment disorders in 19 (35%). Logistic regression analysis showed that a disease-free interval of less than 24 months significantly predicted a diagnosis of major depressive disorder or adjustment disorders (odds ratio 5.28, 95% confidence interval; 1.28–21.8, p=0.02). Conclusions: These results suggest that it is important for all oncology staff to pay careful attention to the psychological health of patients who have been informed of their cancer recurrence, and that some psychosocial intervention is necessary for preventing distress in patients facing early recurrence.
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  • 119
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    Springer
    Breast cancer research and treatment 61 (2000), S. 161-170 
    ISSN: 1573-7217
    Keywords: breast cancer ; cell cycle ; ductal ; histologic subtypes ; lobular
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Infiltrating lobular carcinoma (ILC) and infiltrating ductal carcinoma (IDC) are similar in many respects and their histologic features occasionally overlap. Despite the many similarities, some clinical follow-up data and the patterns of metastasis suggest that ILC and IDC are biologically distinct. Unfortunately, most breast cancer research has focused almost exclusively on the ductal subtype or has not stressed the biologic or molecular genetic distinctions between breast carcinoma subtypes. Several reports have suggested the possibility that ILCs and IDCs differ with respect to expression of antigens involved in proliferation and cell cycle regulation. Therefore, we undertook an immunohistochemical evaluation of cell cycle related antigens in ILCs, including histologic variants thought to represent aggressive neoplasms, and IDCs matched for histologic grade (Modified Bloom–Richardson Grade I). We believe that different antigent expression profiles could elucidate the biological distinctiveness of breast carcinoma subtypes and possibly provide diagnostically relevant information. We studied the expression of the following antigents in 28 archived, formalin-fixed ILCs and 34 well-differentiated IDCs: estrogen receptor (ER), progesterone receptor (PR), Her 2-neu, mib-1, cyclin D1, p27, p53, mdm-2 and bcl-2. 94% of ILCs and 100% of IDCs expressed ER; 75% of ILCs and 76% of IDCs expressed PR; 4% of ILCs and 13% of IDCs expressed c cerb B-2; ILCs and IDCs both expressed mib-1 in approximately 10% of lesional cells; 82% of ILCs and 54% of IDCs expressed cyclin D1; 90% of ILCs and 83% IDCs expressed p27 strongly; 4% of ILCs and 4% of IDCs expressed p53, 25% of ILCs and 33% of IDCs expressed mdm-2; 96% of ILCs and 100% of IDCs expressed bcl-2. None of the apparent differences were statistically significant. The ILC variants demonstrated immunophenotypes that were essentially similar to ILCs of the usual type. We conclude that ILCs and well-differentiated IDCs show similar proliferation and cell cycle control antigen profiles. Despite their unusual histologic features, most ILC variants appear to maintain a characteristic ILC immunophenotype.
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  • 120
    ISSN: 1573-7217
    Keywords: breast cancer ; in vivo tumor models ; Her-2/neu ; metastasis ; SCID mice ; soluble Her-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract HER-2/neu is overexpressed on a variety of human adenocarcinomas and overexpression has been associated with a poor prognosis. For this reason, HER-2 has become an attractive target for immunotherapy. To facilitate testing of anti-HER-2-monoclonal antibodies (MAbs) and immunotoxins (ITs), we have evaluated the in vivo growth and metastatic spread of three HER-2-overexpressing human breast cancer cell lines (BT474, MDA-MB-453 and HCC1954) and one ovarian cancer cell line (SKOV3.ip1) in pre-irradiated male SCID mice using subcutaneous (s.c.), intravenous (i.v.) and intraperitoneal (i.p.) routes of injection. All the cell lines tested grew as s.c. tumors and the growth of BT474 and MDA-MB-453 cells after s.c. injection was improved by co-inoculation with Matrigel. Metastases to the lungs were detectable by PCR or histopathology after s.c. injection of BT474 and to a much lesser extent after s.c. injection of HCC1954, MD-MB-453 and SKOV3.ip1cells. I.P. injection of HCC1954 and SKOV3.ip1 cells produced fatal ascites while i.v. injection of SKOV3.ip1, but not BT474 or MDA-MB-453 cells, resulted in infiltration of lungs and death within 9–11 weeks.
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  • 121
    ISSN: 1573-7217
    Keywords: breast cancer ; chemotherapy ; cohort study ; radiotherapy ; second primary cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objectives and methods.The risk of second primary malignancies (SMN) was studied in a cohort of 4,416 one-year survivors of a breast cancer. The role of the menopausal status and of the initial treatment modalities (surgery, radiotherapy, and chemotherapy) was investigated. Results.Excluding second primary breast cancer and non-melanoma skin cancer, a total of 193 (4.4%) patients developed a SMN between 1973 and 1992, compared with 136 expected (Standardised Incidence Ratio, SIR = 1.4, 95% CI (1.2–1.6)). No trend towards either an increase or a decrease was noted in the SIR with time after treatment (p = 0.2). The greatest increase in the relative risk concerned soft tissue cancers (SIR = 13.0, 95% CI: 6.8–22.3), followed by leukaemia (SIR = 3.1, 95% CI: 1.7–5.0), melanoma (SIR  =  2.7, 95% CI: 1.4–4.8), kidney (SIR = 2.5, 95% CI: 1.2–4.5), ovary (SIR = 2.0, 95% CI: 1.2–3.1) and uterine tumours (SIR = 1.9, 95% CI: 1.4–2.5). The SIR was 3.0 (95% CI 1.8–4.7) in women under 40 at the time of the breast cancer, 1.9 (95% CI : 1.4 – 2.4) in those aged 40–49 and 1.2 (95% CI 1.0–1.4) in those aged 50 or more. In the 2,514 women who had received radiotherapy as initial treatment without chemotherapy, the SIR for all SMN was 1.6 (95% CI: 1.1–2.3) fold higher than in those who had not received radiotherapy as initial treatment. Conclusion.In conclusion, this study confirms the increased risk of second malignancies in women treated for a breast cancer, and particularly in those who were younger at the time of treatment for breast cancer. Our results also suggest that radiotherapy may play a role in the onset of these second lesions.
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  • 122
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; melatonin ; retinoic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It has been established that melatonin (Mlt) and retinoic acid, individually, inhibit the proliferation of the estrogen receptor-alpha (ERα)-positive MCF-7 breast cancer cell line. Our laboratory has previously demonstrated that Mlt and all-trans-retinoic acid (atRA) not only inhibit the proliferation, but also induce apoptosis of MCF-7 cells when used in a sequential regimen of Mlt followed 24 h later by atRA. Using this same MCF-7 breast cancer cell line, we investigated the potential pathways through which apoptosis is being induced. We found that treatment of MCF-7 cells with Mlt for 24 h before the addition of atRA decreased the protein levels of the death suppressor, Bcl-2, and increased, although with different time courses, the levels of the death promoters, Bax and Bak; however, there was no change in the levels of the tumor suppressor gene, p53. MCF-7 cells treated sequentially with Mlt and atRA also demonstrated an enhanced sensitivity to the apoptotic effects of atRA, which did not appear to be due to increased expression of the retinoic acid receptors, RARα or RXRα, but rather to enhanced transcriptional activity of the RARα. These data suggest that the sequential treatment regimen of Mlt and atRA may induce apoptosis by modulation of members of the Bcl-2 family of proteins. Thus, this combinatorial regimen, which reduces the concentration of atRA needed for clinical efficacy while enhancing its anti-tumorigenic activity, could be of great therapeutic benefit, and may, in fact, specifically induce the regression of established breast tumors due to its apoptosis-promoting effects.
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  • 123
    ISSN: 1573-7217
    Keywords: breast cancer ; intravenous digital subtraction angiography ; axillary lymph node metastasis ; neovascularization of lymph nodes ; microvascular density ; antibody to platelet/endothelial cell adhesion molecule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Accurate predication of axillary node status by non-invasive diagnostic method would be of great value in cases of breast cancer. There have been few reports advocating digital subtraction angiography (DSA) as specifically advantageous for the detection of lymph node metastasis. IV (intravenous)-DSA was carried out on 42 patients with breast carcinoma using a DSA system with a matrix of 1024 × 1024×pixels. When a mass became stained in the axilla, it was considered to be metastatic. An immunohistochemical technique with JC70 antibody to platelet/endothelial cell adhesion molecules was used to evaluate the microvascular density (MVD) of the axillary lymph nodes. IV-DSA achieved a 76.2% sensitivity, 85.7% specificity, and 81.0% accuracy. The average MVD with JC70 antibody was 97.7 ± 44.4 in metastatic and 62.9 ± 23.6 in nonmetastatic nodes. MVD was significantly higher in the cancerous than in the noncancerous regions within lymph nodes. The MVD was 105 ± 38.4 in DSA-N(+) cases and was 57.8 ± 21.9 in DSA-N(−) cases, and the difference was statistically significant. In conclusion, IV-DSA is a useful diagnostic modality for detection of axillary lymph node metastasis. This new modality predicts lymph node status by assessing the neovascularization of the lymph node.
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  • 124
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    Cancer causes & control 11 (2000), S. 319-344 
    ISSN: 1573-7225
    Keywords: breast cancer ; endometrial cancer ; fertility drugs ; infertility ; melanoma ; ovarian cancer ; thyroid cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: Over the past decades the use of fertility drugs (FDs) has greatly increased. Recently, the possible association between the use of FDs and risk of cancer has aroused great concern. In this paper, we critically review the available epidemiologic studies. Methods: We identified papers published between 1966 and 1999 that examined FDs and specific causes of subfertility in relation to the risks of cancers of the ovary, breast, endometrium and thyroid, and melanoma. Results: Although present insights into the pathogenesis of hormone-related malignancies suggest a possible association between the use of FDs and the risk of specific cancers, this has not been convincingly demonstrated in epidemiologic studies. With regard to cancer risk in relation to the cause of subfertility, the only consistent association observed is an increased risk of endometrial cancer for women with subfertility due to hormonal disorders. While positive findings in some studies on FDs and ovarian cancer risk have aroused serious concern, the associations observed in most of these reports appear to be due to bias or chance rather than being causal. The most important sources of bias are inadequate confounder control for both parity and causes of subfertility. Conclusions: To discriminate between the possible carcinogenic effects of various ovulation induction regimens, subfertility disorders, and reproductive characteristics associated with subfertility, future studies should include large populations of subfertile women with sufficient follow-up time. In such cohort studies the cause of subfertility should be measured adequately (based on medical records) and information about reproductive characteristics should be collected for all cohort members. Such studies should also include a group of subfertile women with an indication for FD use but not so treated.
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  • 125
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    Cancer causes & control 11 (2000), S. 117-120 
    ISSN: 1573-7225
    Keywords: breast cancer ; cohort ; hydatidiform
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objectives: The etiology of breast cancer is only partially understood. Based on the findings that pregnancies reduce breast cancer risk, a possible inverse association between exposure to the placental hormone human chorionic gonadotropin (hCG) and the risk of breast cancer has been suggested. Hydatidiform mole, a gestational trophoblastic disease, is associated with a high expression of hCG. We performed a population-based cohort study in which women with a history of hydatidiform mole were followed up for future cancer outcomes. Methods: All 3371 women with a notification of hydatidiform mole in the Swedish Cancer Registry between 1958 and 1993 were followed up for future cancer outcomes by record linkages within the registry. Results: In a total of 57,075 person-years of follow-up, 59 women had a diagnosis of breast cancer during follow-up, yielding an overall standardized incidence ratio of 1.3 (95% CI 1.0–1.7). Conclusion: This finding is not consistent with the hypothesis of a protective effect of hCG exposure on breast cancer risk, but rather suggests an adverse association.
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  • 126
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    Breast cancer research and treatment 59 (2000), S. 41-48 
    ISSN: 1573-7217
    Keywords: breast cancer ; bcg-1 ; L19 ; L34 ; MAGE-like ; MLN70 ; subtractive hybridization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A number of approaches have been used to identify genes important in breast cancer. In one approach the genes already shown to be involved in other tumors, such as p53 and Her2neu, were examined. A second approach examined genes detected through genetic screening of families with a high incidence of breast cancer, for example, BRCA-1 and BRCA-2. We used a third approach, subtractive hybridization, to identify and clone genes that were preferentially expressed in breast cancer cells compared to normal mammary epithelium. Instead of analyzing breast cancer cell lines, we examined fresh human breast cancer specimens. By subtracting normal mammary epithelial cDNA from breast cancer cDNA, we were able to clone several genes overexpressed in breast cancer. Two of these genes, L19 and MLN70, were previously reported to be overexpressed in breast cancer. Three of these genes, L19, L34, and MLN70, were localized to a region on chromosome 17 where Her2/neu and BRCA-1 are found. In addition, we isolated a gene we call breast cancer associated gene-1 that was expressed almost exclusively in fresh breast cancer tissue and not in normal mammary epithelium or breast cancer cell lines. We were unable to detect expression of breast cancer associated gene-1 in cell lines from melanoma, renal cell carcinoma, lymphoma, or leukemia. The full-length sequence from two separate breast cancer specimens revealed one amino acid difference compared to the sequence from normal breast epithelial tissue. Further studies are necessary to determine whether these genes contribute to breast cancer development or can be used as therapeutic targets.
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  • 127
    ISSN: 1573-7217
    Keywords: breast cancer ; lobular ; ductal ; conservative surgery ; radiation therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The role of conservative surgery and radiation therapy (CS and RT) in the treatment of patients with infiltrating ductal carcinoma is well established. However, the efficacy of CS and RT for patients with infiltrating lobular carcinoma is less well documented. The goal of this study was to examine treatment outcome after CS and RT for patients with infiltrating lobular carcinoma and to compare the results to those of patients with infiltrating ductal carcinoma and patients with mixed ductal–lobular histology. Methods: Between 1970 and 1986, 1624 patients with Stage I or II invasive breast cancer were treated with CS and RT consisting of a complete gross excision of the tumor and ≥6000 cGy to the primary site. Slides were available for review for 1337 of these patients (82%). Of these, 93 had infiltrating lobular carcinoma, 1089 had infiltrating ductal carcinoma, and 59 had tumors with mixed ductal and lobular feature these patients constitute the study population. The median follow-up time for surviving patients was 133 months. A comprehensive list of clinical and pathologic features was evaluated for all patients. Additional histologic features assessed for patients with infiltrating lobular carcinoma included histologic subtype, multifocal invasion, stromal desmoplasia, and the presence of signet ring cells. Results: Five and 10-year crude results by site of first failure were similar for patients with infiltrating lobular, infiltrating ductal, and mixed histology. In particular, the 10-year crude local recurrence rates were 15%, 13%, and l3% for patients with infiltrating lobular, infiltrating ductal, and mixed histology, respectively. Ten-year distant/regional recurrence rates were 22%, 23%, and 20% for the three groups, respectively. In addition, the 10-year crude contralateral breast cancer rates were 4%, 13% and 6% for patients with infiltrating lobular, infiltrating ductal and mixed histology, respectively. In a multiple regression analysis which included established prognostic factors, histologic type was not significantly associated with either survival or time to recurrence. Conclusions: Patients with infiltrating lobular carcinoma have a similar outcome following CS and RT to patients with infiltrating ductal carcinoma and to patients with tumors that have mixed ductal and lobular features. We conclude that the presence of infiltrating lobular histology should not influence decisions regarding local therapy in patients with Stage I and II breast cancer.
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  • 128
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    Breast cancer research and treatment 59 (2000), S. 1-14 
    ISSN: 1573-7217
    Keywords: breast cancer ; prostate-specific antigen ; prognostic indicators ; tumor markers ; breast cyst ; benign breast disease ; molecular forms of prostate-specific antigen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Although prostate-specific antigen (PSA) is the most valuable tumor marker for the diagnosis and management of prostate carcinoma, it is widely accepted that PSA is not prostate specific. Numerous studies have shown that PSA is present in some female hormonally regulated tissues, principally the breast and its secretions. In this review, we summarize the findings of PSA in the breast, and focus on its potential for clinical applications in breast disease. PSA is produced by the majority of breast tumors and is a favorable indicator of prognosis in breast cancer. Low levels of PSA are released into the female circulation, and while the level of serum PSA is elevated in both benign and malignant breast disease, the molecular form of circulating PSA differs between women with and without breast cancer. These findings indicate that PSA may have potential diagnostic utility in breast cancer. PSA may also have a clinical application in benign breast disease, as both the level and molecular form of PSA differ between Type I and II breast cysts. High levels of PSA have been reported in nipple aspirate fluid (NAF) and recent studies have shown that the concentration of PSA in NAF is inversely related to breast cancer risk, indicating that NAF PSA may represent a clinical tool for breast cancer risk assessment. Thus, PSA represents a marker with numerous potential clinical applications as a diagnostic and/or prognostic tool in breast disease.
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  • 129
    ISSN: 1573-7217
    Keywords: estrogen and progesterone receptor ; S-phase fraction ; tamoxifen ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A Swedish cooperative trial demonstrated that 5 years of adjuvant tamoxifen was more beneficial than 2 years of tamoxifen in the treatment of postmenopausal women with estrogen receptor (ER) positive, early stage, invasive breast cancer. The main aim of the present study was to investigate the importance of progesterone receptor (PgR) and ER concentration levels for patients participating in the trial and still distant recurrence free two years after the primary operation. Subgroup analyses revealed that only patients with ER positive and PgR positive breast cancer had improved distant recurrence free survival (DRFS) by prolonged tamoxifen therapy (p=0.0016). Patients with ER negative and PgR negative as well as ER positive and PgR negative tumors showed no significant effect of prolonged tamoxifen (p=0.53 and p=0.80, respectively). The percentage of ER negative and PgR positive breast cancers was too small (2.2%) for any meaningful subgroup analysis. There was a significant positive trend that the concentration level of PgR (high positive vs. low positive vs. negative) decreased the recurrence rate for those with prolonged therapy. No corresponding pattern was found for the ER content. S-phase fraction did not correlate to the recurrence rate of PgR positive breast cancers. Patients recurring during tamoxifen therapy had receptor negative tumors to a greater extent than those recurring after tamoxifen treatment. In conclusion, prolonged tamoxifen therapy for 5 years instead of 2 years was found to be beneficial for patients with ER positive and PgR positive breast cancer, whereas three extra years of tamoxifen had little or no effect for patients with ER positive but PgR negative tumors as well as for steroid receptor negative patients.
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  • 130
    ISSN: 1573-7276
    Keywords: BRCA1 ; breast cancer ; chemically modified tetracycline ; E-cadherin/catenin ; invasion ; migration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Chemically modified tetracyclines (CMTs) are promising anti-cancer agents. In this study, we found that CMT-3 and CMT-8 showed dose-dependent cytotoxicities in MDA-MB-468 human breast cancer cells. Moreover, both CMT-3 and CMT-8 significantly inhibited in vitro cell migration and invasion at non-cytotoxic concentrations. Anti-invasion and migration potentials of the CMTs were associated with an increased expression of E-cadherin/catenins (α, β and γ-catenin) and tumor suppressor BRCA1. In addition, CMT-3 and CMT-8 abolished or reduced spontaneous and HGF/SF-induced cell invasion and migration in U-373 MG human glioblastoma cells. Our current finding is the first demonstration that CMT-3 and CMT-8 can activate the function of invasion suppressor molecules associated with the suppression of breast cancer cell invasion and migration. Thus, clinical application of CMTs may provide potential benefit for suppression of breast cancer growth, invasion and metastasis.
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  • 131
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    Journal of mammary gland biology and neoplasia 5 (2000), S. 85-94 
    ISSN: 1573-7039
    Keywords: Mannose 6-phosphate/insulin-like growth factor 2 receptor ; tumor suppressor gene ; breast cancer ; loss of heterozygosity ; somatic mutation ; microsatellite instability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R)3 is considereda “candidate” tumor suppressor gene. This hypothesis has been provoked by the identificationof loss of heterozygosity (LOH) at the M6P/IGF2R locus on chromosome 6q26 in breast andliver cancer, accompanied by point mutations in the remaining allele. Somatic mutations incoding region microsatellites have also been described in replication error positive (RER+)tumors of the gastrointestinal tract, endometrium and brain. These genetic data are compelling,but a tumor suppressor gene candidate has to meet functional as well as genetic criteria. Thisreview weighs the evidence and discusses the observations that are necessary to promoteM6P/IGF2R from candidate to bona fide tumor suppressor gene.
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  • 132
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    Journal of mammary gland biology and neoplasia 5 (2000), S. 243-244 
    ISSN: 1573-7039
    Keywords: mouse mammary gland ; human breast ; oncogenes ; breast cancer ; CD-ROM ; histopathology ; ammary development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This article introduces a CD-ROM containing whole-mount and histological images of normal growth and development of both the mouse mammary gland and the human breast. It also covers nonneoplastic lesions and neoplasias in both species including a catalog of lesions in genetically engineered mice. Instructions, with examples, on techniques such as whole-mount preparation, immunohistochemistry, in situ hybridization, and common histological stains are provided. The images are based on full-scale 1996 × 1640 pixel images at 300 pixels/inch and are annotated. Every genetically engineered model has one or more accompanying citations. Tables are provided for orientation and organization. The CD includes zoom capabilities, a search engine, and a help mode.
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  • 133
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    Journal of mammary gland biology and neoplasia 5 (2000), S. 259-270 
    ISSN: 1573-7039
    Keywords: estrogens ; 17β-hydroxysteroid dehydrogenase (17HSD) ; mammary gland ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Estrogen action in the target cells is dependent on estrogen receptor activity and intracellular estrogen concentration, which, in turn, is affected by the serum concentration and local metabolism in these cells. During the reproductive years the main source of estrogens is the ovarian follicles, but in postmenopausal women most of the estrogens are formed in peripheral tissues. 17β-hydroxysteroid dehydrogenases (17HSDs)6 catalyze the reaction between 17β-hydroxysteroids and 17-ketosteroids, and several distinct 17HSD isoenzymes have been characterized. 17HSD type 1 catalyzes the reaction from low-activity estrone to high-activity estradiol. The type 2 enzyme has an opposite activity, thereby reducing the exposure of tissues to estrogen action. 17HSD type 1 is expressed both in steroidogenic tissues and in the target tissues of steroid action, such as normal and malignant breast tissue, where it may be responsible for maintaining the high intracellular estradiol concentration seen in breast cancer specimens. Therefore, 17HSD type 1 inhibitors may be useful in the treatment and/or prevention of estrogen-dependent malignancies, such as breast cancer. This article deals mainly with 17HSD types 1 and 2 and their role in estrogen action in breast tissue.
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  • 134
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    Journal of mammary gland biology and neoplasia 5 (2000), S. 271-281 
    ISSN: 1573-7039
    Keywords: breast cancer ; estrogen receptor ; endocrine therapies ; resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Estrogens have long been recognized as being important for stimulating the growth of a large proportion of breast cancers. Now it is recognized that estrogen action is mediated by two receptors, and the presence of estrogen receptor α (ERα)3 correlates with better prognosis and the likelihood of response to hormonal therapy. Over half of all breast cancers overexpress ERα and around 70% of these respond to anti-estrogen (for example tamoxifen) therapy. In addition, the presence of elevated levels of ERα in benign breast epithelium appears to indicate an increased risk of breast cancer, suggesting a role for ERα in breast cancer initiation, as well as progression. However, a proportion of ERα-positive tumors does not respond to endocrine therapy and the majority of those that do respond eventually become resistant. Most resistant tumors remain ERα-positive and frequently respond to alternative endocrine treatment, indicative of a continued role for ERα in breast cancer cell proliferation. The problem of resistance has resulted in the search for and the development of diverse hormonal therapies designed to inhibit ERα action, while research on the mechanisms which underlie resistance has shed light on the cellular mechanisms, other than ligand binding, which control ERα function.
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  • 135
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    Journal of traumatic stress 13 (2000), S. 301-319 
    ISSN: 1573-6598
    Keywords: PTSD ; breast cancer ; symptom structure ; confirmatory factor analysis ; PCL-C
    Source: Springer Online Journal Archives 1860-2000
    Topics: Psychology
    Notes: Abstract Identification of posttraumatic stress disorder (PTSD) symptoms and diagnoses in survivors of cancer is a growing area of research, but no published data exist regarding the symptom structure of PTSD in survivors of malignant disease. Findings from investigations of the PTSD symptom structure in other trauma populations have been inconsistent and have not been concordant with the reexperiencing, avoidance/numbing, and arousal symptom clusters specified in DSM-IV. The present study employed confirmatory factor analysis to evaluate the extent to which the implied second-order factor structure of PTSD was replicated in a sample of 142 breast cancer survivors. PTSD symptoms were measured using the PTSD Checklist—Civilian Version (PCL-C). Fit indices reflected a moderate fit of the symptom structure implied by the DSM-IV. These findings provide some tentative support for the DSM-IV clustering of PTSD symptoms and for the validity of cancer-related PTSD.
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  • 136
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    Journal of behavioral medicine 23 (2000), S. 15-36 
    ISSN: 1573-3521
    Keywords: genetic risk ; breast cancer ; knowledge ; genetic testing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Psychology
    Notes: Abstract Informed consent for genetic testing for breast–ovarian cancer susceptibility requires that women understand basic concepts about the inheritance of cancer susceptibility and the benefits and risks associated with genetic testing. Women awaiting routine medical services (N = 220) were surveyed about their knowledge of breast cancer and cancer genetics and their perceptions of genetic testing and personal risk. There were no racial differences in median income or mean level of education. Compared to Caucasian women, African American women knew significantly less about breast cancer and about genetic risk for breast cancer. African American women had different psychological, social, and economic concerns as evidenced by how they weighted the benefits and risks of genetic testing. This study is the first to assess several dimensions of informed consent for genetic testing among a sociodemographically diverse group. The findings should enable health professionals to target the African American and lower-income populations with the appropriate education and counseling.
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  • 137
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    Journal of behavioral medicine 23 (2000), S. 367-376 
    ISSN: 1573-3521
    Keywords: optimistic bias ; Health Belief Model ; breast cancer ; prostate cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Psychology
    Notes: Abstract Why do people fail to engage in positive behaviors which will promote their health and well-being? Researchers addressing this question adopt primarily one of two perspectives, drawing either on theories of health behavior, such as the Health Belief Model (HBM), or on theories of risk perception, such as unrealistic optimism. To overcome this compartmentalization, two studies of cancer screening behavior assessed the extent to which unrealistic optimism occurred in relation to each of the elements of the HBM: severity and curability of cancer and the benefits of, and barriers to, having a screening test. Data were collected using telephone interviews, dialing numbers randomly selected from the telephone directory. In the first study 164 women aged 50 to 70 years responded to questions about breast cancer and screening mammography, while in the second study 200 men aged 45 to 60 years responded to questions about prostate cancer and screening using the prostate specific antigen test. Women had an optimistic bias in relation to breast cancer risk and severity and barriers to having a screening mammogram but not in relation to the benefits of screening. For prostate cancer, there was an optimistic bias for all HBM variables: risk and severity of prostate cancer and barriers to and benefits of screening. It was concluded that unrealistic optimism is broader than perceived risk, being evident for all elements of the HBM.
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  • 138
    ISSN: 1573-3599
    Keywords: BRCA1 ; motivation ; satisfaction ; coping, genetic counseling ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Psychology
    Notes: Abstract Women with a strong family history of breast and/or ovarian cancer can now have genetic testing, that may identify mutations associated with increased cancer predisposition. Within the context of a clinical trial evaluating printed educational materials, we examined motivation, satisfaction, coping, and perceptions of genetic counseling and testing among 159 women who underwent pretest counseling and made a testing decision. Ninety-six percent of the participants elected to have BRCA1/2 testing. When making a decision about genetic testing, study participants were concerned less about the potential negative effects that could result from testing than the potential benefits. After counseling, participants said that they felt better able to make decisions that were right for them and that their questions and concerns were adequately addressed during the session. Ninety-five percent of the women were satisfied with their test decision. Participants used a range of strategies to cope with thoughts and feelings about cancer and/or genetic testing immediately following test decision. Results suggest that the genetic counseling session helped women make decisions about testing for BRCA1 and BRCA2, even in the setting of a trial in which all women also received detailed educational materials. Further, the results indicate that future research focusing on perceptions of risks and benefits of testing and of coping strategies immediately following test decision may be warranted.
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  • 139
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    Journal of clinical psychology in medical settings 7 (2000), S. 91-97 
    ISSN: 1573-3572
    Keywords: breast cancer ; breast cancer in men ; male breast carcinoma ; breast cancer treatment ; psychological effects of cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The occurrence of breast cancer in men is rare in comparison to women. Public knowledge that men can get breast cancer and of male breast self-examination are lacking. Research in the course and treatment of breast cancer in men is needed. Men generally present in more advanced stages of breast cancer than women, and have a poorer prognosis. In this article, the epidemiology, common symptoms, diagnostic methods, and current treatment of breast cancer in men are described. Gender differences in presentation and course of illness are discussed. Additionally, the psychological implications of breast cancer for male gender roles and masculine identity are explored. Directions for further investigation are given. Treatment providers are encouraged to educate themselves and their male patients on breast cancer in men and male breast examination techniques so that this disease may be identified earlier in its course and survival rates improved.
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  • 140
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    Clinical social work journal 28 (2000), S. 183-195 
    ISSN: 1573-3343
    Keywords: adolescent ; mother ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract While the literature supports the view that a parent's illness will have an impact on a child, less specific attention has been given to the impact of a mother's breast cancer on her adolescent daughter. In this paper, clinical vignettes derived from interviews with adolescent daughters (ages 12–19) living with mothers who have breast cancer are presented to illustrate some of the concerns daughters have about themselves and their mother's illness. The daughters express anxiety about changes in family roles, but seem more concerned about the potential loss of the mother/daughter relationship. They describe their fears of recurrence of the disease as well as getting the disease themselves. The girls also demonstrate great strength; resilience and hope in the face of the challenges presented by the changes in their lives. Girls who had mothers die of the disease are not included in this article. Implications for treatment are discussed.
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  • 141
    ISSN: 1436-2813
    Keywords: p53 protein ; breast cancer ; lymph node metastasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The p53 expression in invasive breast cancers from 106 patients was correlated with clinicopathological variables to ascertain its usefulness for estimating prognosis. The p53 expression was significantly associated with the number of axillary lymph node metastases and the presence of internal mammary lymph node metastases; however, it was not associated with age, menopausal status, histologic type, or tumor size. Although p53 expression was a significant prognostic factor according to univariate analysis, it did not appear to be an independent prognostic factor according to multivariate analysis. Thus, the prognostic power of p53 expression is likely to be weak and therefore probably of limited clinical value. Nevertheless, the number of patients in our study was small, and we believe that an investigation of a larger series of patients is indicated.
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  • 142
    ISSN: 1436-2813
    Keywords: breast cancer ; extended radical mastectomy ; internal mammary lymph node ; multivariate analysis ; metastasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We performed a new type of en bloc extended radical mastectomy (EXT) as a clinical trial in 118 patients from 1980 through 1985. A variety of conventional radical mastectomies (RDL) were also undertaken in 105 patients from 1973 through 1985. In this retrospective study, univariate and multivariate analyses were performed to compare the results of EXT and RDL. The univariate analysis showed that the 10-year survival rates for the EXT and the RDL groups were 86% ± 3.3% and 77% ± 4.2%, respectively (P = 0.073 with the Cox-Mantel test). For the subgroups stratified according to the status of axillary lymph node involvement, the EXT was significantly better in patients with one to three metastatic axillary lymph nodes (P = 0.016). The adjusted Cox regression analysis revealed that the favorable results of EXT were most encouraging in the patients with one to three metastatic axillary lymph nodes (P = 0.058). Therefore, it is suggested that an EXT may be more advantageous than RDL in selected patients with resectable invasive breast cancer.
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  • 143
    ISSN: 1436-2813
    Keywords: breast cancer ; epidermal growth factor receptor ; prognosis ; lymph node metastasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The association between epidermal growth factor receptor (EGFR) expression, clinicopathological variables, silver-stained nuclear organizer region (Ag-NOR) counts, and patient survival was determined in 93 patients with operable breast cancer. The EGFR expression was found to be significantly associated with the presence and number of axillary lymph node metastases (P = 0.0429), but not with age, menopausal status, tumor size, histologic type or grade, or Ag-NOR counts. In a univariate analysis, a significant difference was also observed in the survival of patients stratified by tumor size (P = 0.0091), histologic grade (P = 0.0352), axillarly lymph node metastases (P = 0.0001), and EGFR expression (P = 0.0263). However, a multivariate analysis revealed that axillarly lymph node metastases was the only strong independent predictor ol'survival (P 〈 0.0001). When axillary lymph node metastases were excluded from the Cox model, the EGFR expression tended to be an independent prognostic factor (P = 0.0558). The results of this study thus indicate that the prognostic value of EGFR expression is limited because the EGFR expression is significantly associated with axillary lymph node metastases.
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  • 144
    ISSN: 1436-2813
    Keywords: breast cancer ; national survey ; breast-conserving surgery ; geographic variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A nationwide survey in Japan of the patients with primary breast cancer from 1989 to 1991 revealed marked changes in the surgical treatment of the disease. During this period, there was a significant trend toward fewer instances of radical and extended radical mastectomies, and an increase in modified radical mastectomies and breast-conserving surgery. The percentage of breast-conserving surgery for the early-stage disease increased from 6.8% to 12.7%. Among the types of operations for breast-conserving surgery, quadrantectomy was used for 51.5% of the cases, while either a partial mastectomy or a subcutaneous mastectomy was used for 18.2% and 18.9%, respectively; a lumpectomy was performed in 10.9% of the cases. As for the proportion of patients receiving radiation therapy after breast-conserving surgery, 77% of those undergoing lumpectomy received radiation in contrast to only 43% of the patients undergoing quadrantectomy. According to the data from 1991, we also found that breast-conserving surgery was performed more often in larger cities and urban areas in Japan. As a result, we found that substantial changes in the treatment of localized breast cancer had taken place from 1989 to 1991. Regarding the details of breast-conserving surgery, however, some variation still remains in spite of the publication of numerous clinical trials.
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  • 145
    ISSN: 1436-2813
    Keywords: breast self-examination ; questionnaire survey ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Using a questionnaire survey, we analyzed the relationship between the frequency of breast self-examination (BSE) and the clinical stage and course of breast cancer in Japanese patients. BSE had been performed monthly by only 5.4% of the patients (M group), occasionally by 35.4% (O group), and not at all by 59.2% (N group). There was a positive relationship between more frequent BSE and an earlier clinical stage, the percentages of Tis/stage 0 and I for the M, O, and N groups being 83%, 44%, and 36%, respectively (P〈0.05). The mean maximum tumor diameters for the three groups were 1.7cm, 2.5cm, and 3.0cm, respectively. The tumor size in the M and O groups was significantly smaller than that in the N group atP〈0.01 andP〈0.05, respectively. The percentages of patients in the M, O, and N groups who underwent breast-conserving therapy were 42%, 11%, and 19%, respectively, with patients who had performed monthly, BSE more frequently undergoing breast-conserving therapy (P〈0.05). At a median follow-up time of 34 months, 0%, 3.8%, and 7.6% of the patients from the M, O, and N groups, respectively, had died of breast cancer, the overall survival curve of the M group being significantly better than that of the N group (P〈0.01). This retrospective study suggests the positive correlation of BSE frequency with earlier detection, and a more favorable clinical course in Japanese breast cancer patients.
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  • 146
    ISSN: 1436-2813
    Keywords: parathyroid hormone-related protein ; breast cancer ; skeletal metastases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The relationship between the expression of parathyroid hormone-related protein (PTHrP) by breast cancer and skeletal metastases, was investigated using a monoclonal antibody against human PTHrP (4133). The immunohistochemical localization of PTHrP was studied in sections of formalin-fixed, paraffin-embeded tissues from 28 breast cancers obtained surgically between 1980 and 1985. Of the 28 patients, 12 developed skeletal metastases, 8 developed lung metastases, and the other 8 were alive and disease-free at the time of this study. Sixteen of the 28 (57%) tumors showed positive immunoreactivity to 4133, the PTHrP positive ratio being 83% in the patients who developed skeletal metastases, 38% in those who developed lung metastases, and 38% in those without recurrence, respectively. Thus, a significantly higher proportion of the patients who developed skeletal metastases were positive for PTHrP than the other two groups (P 〈 0.05). Furthermore, the level of positive staining was strongly related to positivity for estrogen and progesterone receptors (P 〈 0.01). These results are consistent with the hypothesis that PTHrP might be necessary for metastases to erode bone and grow in skeletal sites, and its expression could be related to certain hormones.
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  • 147
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    Journal of behavioral medicine 17 (1994), S. 523-534 
    ISSN: 1573-3521
    Keywords: breast self-examination ; compliance ; breast cancer ; positions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Psychology
    Notes: Abstract The present study examined compliance with the three recommended breast self-examination (BSE) positions over a 6-month follow-up period. An ongoing behavioral measure that provided information about the type of exam performed during each BSE occasion was employed. Results indicated that adherence to all three position types was obtained in only 40% of the exams. Forty-two percent of exams were comprised of only one position, with the supine position being the most frequently practiced exam type. Implications of these results with regard to BSE research and current breast cancer screening recommendations are discussed.
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  • 148
    ISSN: 1573-4986
    Keywords: breast cancer ; fucose ; haptoglobin ; ovarian cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract There is increasing evidence for changes in fucosylation in cancer. Previously, we showed that the fucose-specific lectin,Lotus tetragonolobus, extracts an abnormal form of haptoglobin (Hp) from cancer sera. This study investigates the monosaccharide content of Hp obtained from women with ovarian and breast cancer at different stages of their disease. In both cancers, Hp fucose was low when the disease was benign or in remission and much higher when the disease was progressive. This occurred whether the data was expressed per mole of protein or per three mannose residues. Changes in other monosaccharides were minor compared with fucose. There were small increases in theN-acetylglucosamine and galactose content (per three mannoses) in ovarian cancer, suggesting that some glycan chains have increased branching. The latter was independent of disease activity which may be due to some indirect cause such as cytotoxic therapy or an inflammatory response. When ovarian cancer patients were in remission, the number of glycosylation sites on Hp was reduced. Hp isolated from patients with early, but not advanced breast cancer also appeared to have increased glycan branching. The increased fucosylated Hp may interfere with fucose-mediated adhesion reactions of cancer cells.
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  • 149
    ISSN: 1573-0646
    Keywords: cis-platinum ; mitoxantrone ; breast cancer ; phase I-II trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The Southwest Oncology Group studied the response rate and toxicity of mitoxantrone (7.5 or 10 mg/m2 to 12.0 mg/m2) and cis-platinum (100 mg/m2) in 30 patients with advanced breast cancer as second-line therapy. There were 2 partial responses in 29 eligible patients. Toxicity was considerable, with 27 patients having grade 3 or 4 toxicity. Grade 3–4 toxicity included vomiting, thrombocytopenia, granulocytopenia, leukopenia and anemia. The combination of mitoxantrone plus cis-platinum has minimal activity as second-line therapy in metastatic breast cancer.
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  • 150
    ISSN: 1573-0646
    Keywords: breast cancer ; dipyridamole ; mitoxantrone ; 5-FU ; leukovorin ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m2 by mouth every 6 h (700 mg/m2/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m2 was given intravenously immediately prior to 5-FU 375 mg/ m2 intravenously on days 1–5. Mitoxantrone 6 mg/m2 was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m2 days 1–2, 5-FU 375 mg/m2 days 1–2, mitoxantrone 6 mg/m2 on day 2, and dipyridamole 175 mg/m2 every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.
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  • 151
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    Investigational new drugs 12 (1994), S. 333-336 
    ISSN: 1573-0646
    Keywords: piroxantrone ; oxantrazole ; anthrapyrazoles ; NSC-349174 ; Dup 942 ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirty-two eligible patients with advanced metastatic breast cancer who had received no more than 1 prior chemotherapy regimen for metastatic disease (16 had received prior doxorubicin) were treated with piroxantrone at a dose of 120 mg/m2 intravenously every 21 days. In the twenty-seven patients evaluable for response, two partial responses were seen. Toxicities observed were primarily hematologic with grade 3 or greater granulocytopenia occurring in 34% of the patients. One patient developed symptomatic congestive heart failure at a total cumulative dose of 960 mg/m2. We conclude that piroxantrone given at this dose and schedule has minimal activity in patients with metastatic breast cancer.
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  • 152
    ISSN: 1573-7276
    Keywords: breast cancer ; cell proliferation ; invasion ; migration ; 1α ; 25-dihydroxyvitamin D3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Using the Boyden chamber invasion assay, the effect of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] on the invasiveness of the highly invasive, oestrogen receptor-negative human breast cancer cell line MDA-MB-231 was examined. The MDA-MB-231 cells were shown to contain high-affinity receptors for 1α,25(OH)2D3 with a Kd of 1.5 × 10−11 M. When the cells were treated with 1α,25(OH)2D3 for 4 days before the assay was performed, a dose-dependent inhibition of their invasive potential was demonstrated. Fifty per cent inhibition of invasion was obtained with a concentration of 13 pM of 1α,25(OH)2D3. However, when the cells were treated for only 6 h during the assay, no inhibitory effect was seen. The process of migration was also affected by treatment with 1α,25(OH)2D3 for 4 days, although the inhibition was not of the same magnitude as seen for the invasion. Fifty per cent inhibition of migration occurred at a concentration of 3.2 nM of 1α,25(OH)2D3 (250 times higher than in the invasion assay). Inhibition of invasion and migration was not due to the known anti-proliferative effect of 1α,25(OH)2D3, as no growth reduction could be demonstrated with treatment up to 5 days. Based on the present investigation it can therefore be concluded that 1α,25(OH)2D3 is able to inhibit tumour cell invasiveness by a mechanism which is not exclusively based on its anti-proliferative and anti-migrative effects.
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  • 153
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    Journal of neuro-oncology 21 (1994), S. 159-170 
    ISSN: 1573-7373
    Keywords: paraneoplastic syndrome ; sensorimotor neuropathy ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Paraneoplastic sensorimotor neuropathy occurs in association with many different types of cancer. The clinical findings are heterogeneous, and the pathogenesis is unknown. We have encountered 9 women with breast cancer and shared neurological features that suggest a distinct paraneoplastic syndrome. The syndrome is characterized by upper and lower extremity paresthesias and numbness, itching, muscle weakness and cramps, and in some, radicular symptoms and signs. Serum and CSF inflammatory changes suggested an immune pathogenesis but none had detectable antibodies directed at nervous system elements. Six patients presented with neuropathy 2 months to 8 years before the discovery of the breast cancer. In 7 the neoplastic disease was localized to the breast and axillary lymph nodes. The neurologic course was chronic in all, and while symptoms were annoying, disability was minimal until late. One improved transiently with plasmapheresis, and three had mild transient improvement with treatment of the cancer. Recognition of this paraneoplastic syndrome may forewarn the physician of an underlying breast malignancy.
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  • 154
    ISSN: 1573-7225
    Keywords: A-bomb survivors ; breast cancer ; ionizing radiation ; Japan ; reproductive history
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Three breast cancer risk factors were evaluated in terms of their interactions with radiation dose in a case-control interview study of Japanese A-bomb survivors. Cases and controls were matched on age at the time of the hombings and radiation dose, and dose-related risk was estimated from cohort rather than case-control data. Each factor—age at first full-term pregnancy, number of deliveries, and cumulative lactation period summed over births—conformed reasonably well to a multiplicative interaction model with radiation dose (the additive interactive model, in which the absolute excess risk associated with a factor is assumed to be independent of radiation dose, was rejected). An important implication of the finding is that early age at first full-term pregnancy, multiple births, and lengthy cumulative lactation are all protective against radiation-related, as well as baseline, breast cancer. Analyses by age at exposure to radiation suggest that, among women exposed to radiation in childhood or adolescence, a first full-term pregnancy at an early agefollowing exposure may be protective against radiation-related risk.
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  • 155
    ISSN: 1573-7217
    Keywords: breast cancer ; epidermal growth factor receptor ; estradiol receptor ; progesterone receptor ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In a study on 214 patients with primary breast cancer (median follow-up 8.5 yr, maximum follow-up 15 yr), EGF-R was negatively correlated to estrogen receptor and progesterone receptor, whereas no association was found with age, lymph node status, and tumor size. Initially, after a follow-up of 5 yr, there was a tendency to a significant association between EGF-R levels and tumor recurrence rate (p=0.08). Patients with tumors containing intermediate levels of EGF-R experienced a longer relapse-free survival (RFS) than did patients with tumors possessing lower or higher levels of EGF-R. This effect was most pronounced in the subgroup of patients with positive axillary lymph nodes. However, after 10 yr follow-up, this association appears to be lost (p=0.28) as shown in this update. A similar phenomenon was observed for the ER. While at 5 yr follow-up ER status had significant prognostic value (p=0.01), at 10 yr follow-up this significance also appears to be lost (p=0.40). However, tumor size, lymph node status, grade, and PgR status maintained significant prognostic value by univariate analysis. Based on 40 separate studies comprising 5232 patients, the mean percentage of EGF-R positivity reported in breast cancer is 45% (range 14–91%). Nine out of 15 different studies showed in some way a significant negative association between EGF-R and RFS by univariate analysis, and 2 others showed a tendency to such a relationship. Of 7 studies applying multivariate analysis, two demonstrated an independent prognostic value of EGF-R for RFS and two others a tendency to a significant correlation, whereas three did not. It may be concluded that EGF-R status has more or less prognostic value in patients with primary breast cancer, but the prognostic power decreases with longer follow-up. Of great clinical significance is the association of EGF-R with hormone resistance. Therefore EGF-R status can be used for selection of type of treatment. Finally, EGF-R might be useful as a target for new treatment modalities.
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  • 156
    ISSN: 1573-7217
    Keywords: breast cancer ; 1,25-dihydroxyvitamin D3 ; growth inhibition ; MCF-7 ; tamoxifen ; ZR-75-1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the present study we assessed the effect of combined treatment with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and tamoxifen (TAM) on the growth of estrogen-responsive (MCF-7) and estrogen-dependent (ZR-75-1) human breast cancer cells. Both basal and 17β-estradiol (17β-E2)-stimulated growth were studied. 1,25-(OH)2D3 (10−10 – 10−7 M) time- and dose-dependently inhibited basal growth of MCF-7 cells, with growth arrest at 10−7 M. Also, 17β-E2-stimulated growth of MCF-7 and ZR-75-1 cells was inhibited by 1,25-(OH)2D3 in a time- and dose-dependent manner. TAM inhibited 17β-E2-stimulated growth of both cell lines and at high concentration (10−6 M) it also inhibited basal growth of MCF-7 cells. 10−6 M TAM together with 1,25-(OH)2D3 resulted in a further inhibition of basal (MCF-7 cells) as well as 17β-E2-stimulated proliferation (MCF-7 and ZR-75-1 cells) compared to the inhibition by these agents alone. TAM in combination with 10−7 M 1,25-(OH)2D3 resulted in growth arrest of 17β-E2-stimulated growth of MCF-7 cells. The inhibition of basal and 17β-E2-stimulated growth of MCF-7 cells was additive at early time points (4 days), but less than additive at later time points (8–10 days). It was demonstrated that with co-treatment of MCF-7 cells an equipotent inhibition of basal growth could be reached with lower concentrations of 1,25-(OH)2D3, compared to treatment with 1,25-(OH)2D3 alone. Studies with low concentrations (〈 10−7 M) of TAM revealed a partial estrogenic effect, i.e. stimulation of MCF-7 proliferation in the absence of 17β-E2. This effect, which may resemble TAM-induced tumor flare, was completely prevented by co-treatment with a low concentration of 1,25-(OH)2D3 (10−9 M). Together, these results demonstrate the potent inhibition of breast cancer cell proliferation by 1,25-(OH)2D3 combined with TAM and indicate a potential benefit of combining these agents for the treatment of breast cancer.
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  • 157
    ISSN: 1573-7217
    Keywords: breast cancer ; prognosis ; gene amplification ; PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The prognostic value of oncogene amplification and conventional clinicopathological features was determined in consecutive breast cancers detected during 5 months in 1975–1976 in 4 Swedish counties. Material was collected from 162 of the 179 patients and tumor size, nodal status, FSH, estrogen/progesterone receptor status, DNA ploidy and S-phase fraction determined. Tissues remaining from 80 patients were stored frozen until 1991, when amplification of the oncogenes c-erb-B2 and int-2 was determined. We show that c-erb-B2 amplification (but not int-2 amplification) and positive axillary nodal status show prognostic significance for both survival and relapse-free survival in univariate and multivariate analysis. The other examined factors showed no significance.
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  • 158
    ISSN: 1573-7217
    Keywords: breast cancer ; gene amplification ; PCR ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The polymerase chain reaction (PCR) is a powerful tool to examine genetic alterations in tumor samples. We describe a simple, rapid, nonisotopic PCR method to semi-quantitatively determine the number of gene copies in human formalin-fixed paraffin-embedded tissue. The procedure is exemplified by analysis of 15 years old breast cancer samples to determine the presence of amplification of c-erb-B2. The samples were obtained from routine specimens kept in pathological archives. Patients with amplified samples showed a poor prognosis, both for recurrences and death in breast cancer.
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  • 159
    ISSN: 1573-7217
    Keywords: breast cancer ; carcinoma-associated glycoproteins ; monoclonal antibody 83D4 ; O-glycosylation ; Tn antigen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The Tn determinant (GalNAcα-O-Ser/Thr) is expressed by about 90% of human carcinomas, but is cryptic in most normal human tissues. A murine monoclonal antibody (MAb) 83D4, developed following immunization with human breast carcinoma cells, reacts with a Tn-related epitope. In the present study we characterized the glycoprotein antigen identified by 83D4 in the human breast carcinoma cell line MCF-7. We further showed that the 83D4 antigenic determinant is masked in human milk fat globule membranes (HMFGM), and can be exposed upon mild m-periodate treatment after desialylation. Western-blot analysis resolved the 83D4 antigen from MCF-7 into two main components of 120–190 kD and 〉 500 kD respectively. Non equilibrium pH gradient electrophoresis/SDS PAGE revealed the acidic nature of the reactive glycoproteins (pI 4.43–4.70). 83D4 antigenic activity resolved by CsCl gradient ultracentrifugation layered on a wide range of densities (1.30–1.46 g/ml) including typical densities of mucin-like glycoproteins but also lower densities. The amino acid composition of the antigen, relatively rich in serine but poor in threonine and proline, confirmed the divergence from other mucin-like carcinoma-associated glycoproteins. Dicarboxylic amino acids were abundant, accounting in part for the acidic nature of the molecules. ELISA and Western-blot analysis of the subcellular fractions from MCF-7 cells revealed that the 83D4 antigen is mainly contained in plasma membranes (85%) from which it may be resolved into two broad bands (slow and fast migrating components). These results provide information on a group of breast carcinoma associated glycoproteins related to but different from typical mucins, and provide data on alteration of O-glycosylation in tumor cells.
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  • 160
    ISSN: 1573-7217
    Keywords: DNA flow cytometry ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ninety-one cases of primary breast cancers and their nodal metastases were examined with DNA flow cytometry. No differences were found between the stemline distributions in the primary tumors and nodal metastases. At both sites stemlines clustered around a DNA index of 1.0 (33–40% of cases) and 1.8. The mean S-phase fractions were 7.9 in primary tumors versus 5.6% in nodal metastases (p = 0.02); this difference was also observed if the analysis was restricted to cases with DNA aneuploidy at both sites (10.2 versus 7.6%, p = 0.04). Our results indicate that axillary nodal ploidy and proliferation reflect primary tumor characteristics rather than displaying changes associated with selection during the lymphatic metastatic process. Lymph nodes may have a suppressive effect on the proliferation of tumor cells.
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  • 161
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    Breast cancer research and treatment 31 (1994), S. 129-138 
    ISSN: 1573-7217
    Keywords: breast cancer ; tamoxifen ; drug resistance ; estrogen receptor mutant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The nonsteroidal antiestrogen tamoxifen (TAM) is the most commonly used endocrine treatment for all stages of breast cancer in both pre- and postmenopausal women. However, the development of resistance to the drug is common, as most patients treated with TAM eventually experience a recurrence of tumor growth. One of the potential mechanisms of treatment failure is the acquisition by the tumor of the ability to respond to TAM as a stimulatory rather than inhibitory ligand. We (Gottardis and Jordan, Cancer Res 48: 5183-5187, 1988; Wolfet al., J Natl Cancer Inst 85: 806-812, 1993) and others (Osborneet al., Eur J Cancer Clin Oncol 23: 1189-1196, 1987; Osborneet al., J Natl Cancer Inst 83: 1477-1482, 1991) have extensively described the reproducible development of TAM stimulated growth in a laboratory model system using MCF-7 human breast cancer cells grown as solid tumors in athymic mice. In this paper we report on the isolation of an estrogen receptor (ER) from a TAM stimulated tumor (MCF-7/MT2) which contains a point mutation that causes a tyrosine for aspartate substitution at amino acid 351 in the ligand binding domain. The mutant appears to the major form of ER expressed by this tumor. We also report that only wild type ER was detected in three other TAM stimulated MCF-7 tumor variants, suggesting that multiple mechanisms are possible for the development of TAM stimulated growth. The implications of these findings are discussed.
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  • 162
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    Breast cancer research and treatment 31 (1994), S. 117-127 
    ISSN: 1573-7217
    Keywords: breast cancer ; tamoxifen ; drug resistance ; MCF-7 sublives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The non-steroidal antiestrogen tamoxifen (TAM) is successfully used to treat all stages of breast cancer in both pre- and postmenopausal women. Unfortunately, most women treated with TAM eventually develop resistant tumor recurrences which require intervention with a second-line endocrine therapy, or cytotoxic chemotherapy if the recurrence is completely endocrine insensitive. There is evidence that some recurrences may in fact be TAM stimulated. MCF-7 human breast cancer cells grown as solid tumors in athymic mice chronically treated with TAM reproducibly develop a TAM stimulated phenotype (Osborneet al., Eur J Cancer Clin Oncol 23: 1189-1196, 1987; Gottardis and Jordan, Cancer Res 48: 5183-5187, 1988; Osborneet al., J Natl Cancer Inst 83: 1477-1482, 1991; Wolfet al., J Natl Cancer Inst 85: 806-812, 1993). Tumors of this type may provide a useful model for a subset of therapeutic failures in the clinic. Therefore, we have extensively studied this model in an attempt to define the mechanism or mechanisms leading to TAM stimulated growth. In this paper we describe the characteristics of 4 TAM stimulated MCF-7 tumor variants. All of these tumors are growth stimulated by TAM, but vary in their response to estradiol (E2) treatment, and grow poorly in placebo treated hosts. All tumor variants express estrogen receptor (ER) RNA and protein, which at the RNA level appear to be down regulated by TAM, and to a greater extent by E2. All tumors also express epidermal growth factor receptor (EGFR) RNA, which is down regulated by TAM, and further down regulated by E2. However, among the tumor variants analyzed, ER and EGFR levels appear to be inversely related. Further, despite the expression of ER by all 4 TAM stimulated tumor variants, E2 induction of progesterone receptor expression is very weak or entirely absent.
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  • 163
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    Breast cancer research and treatment 31 (1994), S. 227-236 
    ISSN: 1573-7217
    Keywords: breast cancer ; epidermal growth factor receptor ; gene expression ; hormone-indepence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Overexpression of the EGF receptor in breast cancer correlates with poor prognosis and failure on endocrine therapy for both ER−/EGFR+ and ER+/EGFR+ tumors, suggesting a role for EGFR in the progression to hormone independence. The identification of specific DNase I hypersensitive site patterns for the EGFR gene in ER+ vs. ER− cells implicates regions of the EGFR first intron in up-regulation of EGFR, while estrogen regulation studies indicate the involvement of a repressor(s) in the maintenance of low levels of EGFR. Based on these findings, a multi-step model is proposed for the progression of breast cancer from a hormone-dependent, ER+/EGFR- phenotype to an aggressive, hormone-independent, ER−/EGFR+ stage.
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  • 164
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    Breast cancer research and treatment 31 (1994), S. 285-299 
    ISSN: 1573-7217
    Keywords: metabolism ; magnetic resonance spectroscopy ; phospholipid biosynthesis ; phosphorus-31 MRS ; proton MRS ; carbon-13 MRS ; hormonal effects ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The basis for the use of nuclear magnetic resonance (NMR) spectroscopy as a tool to study the metabolism of breast cancer cells is described. The differences between proton (1H), carbon (13C), and phosphorus (31P) NMR methods is explained, and the techniques of cell extracts, cell suspensions and perfusion methods for cells are detailed. In order to perfuse cells they are preferably trapped in a gel matrix, either in the form of a thread or a bead. The gel must have appropriate properties that enables efficient oxygenation and availability of nutrients and drugs. The metabolic effects of perfusion of breast cancer cells with nutrients, drugs, and hormones are reported, and the clinical relevance of these results and methods are outlined.
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  • 165
    ISSN: 1573-7217
    Keywords: breast cancer ; prognosis ; growth fraction ; Ki-67 ; TLI
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In situ determination of proliferative activity was performed on 184 consecutive primary invasive breast cancers. Methods used were monoclonal antibody Ki-67 in immunohistochemistry and thymidine labeling index. Tumor proliferation correlated between both methods (p = 0.0001). For thymidine labeling index and Ki-67, respectively, significant correlations existed with histologic tumour grade and steroid hormone receptors (Tumor grade: TLIp = 0.0001; Ki-67 p = 0.0001. ER-ICA: TLI = 0.0001; Ki-67 p = 0.014. PgR-ICA: TLIp = 0.0001; Ki-67 p = 0.0008). For thymidine labeling index a significant correlation was demonstrated for overall survival (p = 0.001) and recurrence free survival (p = 0.01). No statistical significance was observed for clinical outcome and Ki-67 (overall survival p = 0.18; recurrence free survival p = 0.1). None of the factors, TLI or Ki-67, was an independent prognostic factor as demonstrated by multivariate analysis.
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  • 166
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    Breast cancer research and treatment 29 (1994), S. 3-9 
    ISSN: 1573-7217
    Keywords: growth factors ; receptors ; tyrosine kinase ; breast cancer ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The type 1 family of growth factor receptors includes the EGFR, c-erbB2, c-erbB3, and c-erbB4. All four members of the family are expressed in breast cancer. The EGFR gene and more frequently the c-erbB2 gene are amplified in a proportion of cases. In addition to increased expression as a result of gene amplification, overexpression of perhaps all of the receptors also appears to occur, probably as a result of increased mRNA transcription. Overexpression may have prognostic value and may predict response to current therapies. Finally these GFR proteins represent targets for new types of chemotherapeutic agents.
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  • 167
    ISSN: 1573-7217
    Keywords: epidermal growth factor receptor ; prognostic factor ; c-erbB-2 ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have conducted two series of studies, a biochemical study and an immunocytochemical study, to investigate the role of epidermal growth factor receptor (EGFR) expression in primary breast cancer patients. In the biochemical study, a consecutive 115 patients were included and EGFR was measured by a competitive binding assay with multipoint Scatchard analysis. In the immunocytochemical study comprising 126 patients, EGFR status was determined by immunostaining with anti-EGFR antibody EGFR1. Several agreements were found from these two studies. EGFR status was inversely correlated with estrogen receptor (ER) status. No significant correlation was found between EGFR status and tumor size, nodal metastases, or the expression of c-erbB-2 protein. Ki-67 immunoreactivity, a cellular proliferation marker, was enhanced in EGFR positive tumors over EGFR negative tumors, suggesting a linkage of EGFR expression to cellular proliferative activity. Post-operative follow up showed that relapse-free survival for EGFR positive patients was significantly worse than that for EGFR negative patients, particularly in node-positive patients. Multivariate analysis demonstrated a significance of EGFR status as an independent prognostic indicator in primary breast cancer. The group expressing EGFR and c-erbB-2 protein indicated a particularly high risk for relapse.
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  • 168
    ISSN: 1573-7217
    Keywords: breast cancer ; endocrine therapy ; epidermal growth factor receptor ; estrogen receptor ; Ki67 ; c-erbB-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 106 previously untreated breast cancer patients have been immunohistochemically analysed for EGF-R, ER, Ki67, and c-erbB-2 product. All patients received assessable endocrine therapy following disease progression. Significant associations were observed between EGF-R and ER (inverse) and Ki67 (direct). No association was observed between EGF-R and the c-erbB-2 product. EGF-R expression was significantly associated with the loss of endocrine sensitivity in breast cancer. This was observed in both ER positive and negative disease. In ER positive breast cancers, EGF-R expression had no significant influence on the quality of tumour remissions. Further sub-classification of the ER/EGF-R data by Ki67 immunostaining showed that in ER+/EGF-R- disease, increasing proportions of Ki67 positive cells were associated with a decline in the numbers of women experiencing good quality tumour remissions. A similar trend was also observed in ER+/EGF-R+ tumours. The presence of c-erbB-2 protein product did not influence endocrine sensitivity in any of the ER/EGF-R sub-groups.
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  • 169
    ISSN: 1573-7217
    Keywords: breast cancer ; dehydroepiandrosterone ; DHEA ; intracrinology ; prevention
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The concentration of serum dehydroepiandrosterone sulfate (DHEA-S) and DHEA decreases markedly during aging, and low circulating levels of DHEA have been associated with a higher incidence of breast cancer in women. Using 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat as model, we have studied the effect of increasing serum levels of DHEA released from Silastic implants on the incidence of these tumors in the rat. Treatment with increasing doses of DHEA leading to serum DHEA levels comparable to those observed in normal adult women (7.1 ± 0.6 nM and 17.5 ± 1.1 nM) caused a progressive inhibition of tumor development from 68% bearing tumors in control animals to 22% and 11%, respectively. The average tumor area per rat decreased from 2.81 cm2 in intact control animals to 0.96 and 0.09 cm2 in the groups treated with the same doses of DHEA, respectively. The present data indicate that circulating levels of DHEA similar to those found in normal adult premenopausal women exert a potent inhibitory effect on the development of DMBA-induced mammary tumors in the rat, thus suggesting the possibility of a new and more physiological approach for the prevention of breast cancer in women.
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  • 170
    ISSN: 1573-7217
    Keywords: breast cancer ; TGF-α ; TNF-α ; monoclonal antibody ; immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The function of different growth factors in the development and progression of malignant tumors and the role of cytotoxic cytokines in the host response generated against neoplasms have been recently studied. Anti-TGF-α and anti-TNF-α monoclonal antibody families have been developed and characterized previously by our laboratory. Libraries of anti-TGF-α and anti-TNF-α monoclonal antibodies were selected for equal immunoreactivity both in native (frozen) and in formaldehyde fixed, paraffin embedded histological sections. No differences were found between native and fixed samples demonstrated in 10 cases in the present prospective study. Retrospective investigation was performed in 35 histopathological specimens of breast cancer patients detailed clinically and observed during 5 years after the surgical treatment. Correlation between TGF-α and/or TNF-α expression and clinical staging - TNM score, lymph node metastasis, tumor recurrence and survival time - was analyzed. According to our present study, the TGF-α positive patients had worse clinical prognosis than the TNF-α positive and double positive cases during long term observation.
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  • 171
    ISSN: 1573-7217
    Keywords: breast cancer ; doxorubicin ; chemotherapy ; ifosfamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ifosfamide has single agent activity in advanced breast cancer and may potentiate the activity of doxorubicin. The combination of ifosfamide 5 g/m2 and doxorubicin 40 mg/m2 every 3 weeks for 4 cycles was used to treat 77 patients with advanced breast cancer. Fifty three patients had not received prior chemotherapy. All patients had one or more poor prognostic features, including tumor expression of epidermal growth factor receptor in 11/12 tested. The overall response rate was 74% (95% confidence intervals 62%-83%). The median survival was 9.4 months. The principal toxicities were febrile neutropenia and ifosfamide encephalopathy each in 6% of patients. A high percentage of the projected dose intensity was administered. This is a highly active combination with acceptable toxicity in advanced breast cancer, although the long term survival remains poor. Further exploration of ifosfamide in combination chemotherapy for advanced breast cancer is warranted.
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  • 172
    ISSN: 1573-7217
    Keywords: breast cancer ; ornithine decarboxylase ; polyamines ; estradiol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies have shown that natural polyamines - putrescine, spermidine, and spermine - play a key role in the mechanism of action of estrogens in breast cancer. Ornithine decarboxylase (ODC) is the first enzyme of the polyamine biosynthetic pathway. To examine estrogenic regulation of polyamine biosynthesis in breast cancer, we measured ODC mRNA, ODC activity, and polyamine levels in G1 synchronized MCF-7 cells. ODC mRNA and activity increased four-fold over that of cells in G1 phase between 8 to 16 h after the addition of estradiol. Polyamine levels showed a sharp increase by 8 h after the addition of estradiol and decreased by 12 h. We further examined whether synthetic homologs of putrescine or spermidine could replace natural polyamines in supporting MCF-7 cell growth. Treatment of MCF-7 cells with 1 mM difluoromethylornithine (DFMO), an inhibitor of ODC, suppressed putrescine, spermidine, and spermine levels by 74, 78, and 10%, respectively, within 48 h. Cells treated with DFMO for 48 h were supplemented with either putrescine or its homologs or spermidine or its homologs. Diaminopropane, diaminobutane (putrescine), and diaminopentane were capable of fully or partially reversing the growth inhibitory effects of DFMO, whereas diaminoethane had no significant effect. Among a series of triamines, H2N(CH2)nNH(CH2)3NH2 (where n = 2 to 8; abbreviated as APn n = 4 for spermidine, or AP4), spermidine was most effective in reversing the effects of DFMO, whereas compounds with shorter or longer methylene bridging regions were less effective. AP8 was ineffective in reversing the growth inhibitory effects of DFMO. At 10 µM concentration, AP8 also inhibited DNA synthesis by 66%, as measured by [3H]-thymidine incorporation. These data show that MCF-7 cells have a strong requirement for polyamines for their growth and that estradiol stimulates the polyamine cascade by inducing the ODC mRNA level. Our results also suggest that polyamine homologs such as AP8 might be potentially useful in breast cancer therapy.
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  • 173
    ISSN: 1573-7217
    Keywords: aromatase inhibitor ; breast cancer ; growth factors ; hormonal treatment ; insulin-like growth factor I ; postmenopause
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A number of endocrine treatments for advanced breast cancer seem to affect serum insulin-like growth factor I (IGF-I). The aim of our study was to investigate IGF-I levels in 33 postmenopausal patients with metastatic disease receiving the selective aromatase inhibitor 4-hydroxyandrostenedione: 250 mg (16 patients) or 500 mg (17 patients) i.m. fortnightly. Blood samples were collected before, and at one month and 3 months after the beginning of treatment for radioimmunoassay determinations. The median patient age was 56 and 60 years in the 250 and 500 mg groups respectively. Most patients had a disease free interval ≥ 2 years and were oestrogen receptor positive. Objective responses were obtained in 3 patients (complete response, 1) in the 250 mg group, and in 7 patients (complete response, 3) in the 500 mg group. No significant IGF-I variations were seen in the 250 mg group, whereas a significant increase after 3 months (181.57 ± 84.78 ng/mlversus 272.47 ± 213.22 ng/ml, p = 0.0032) was observed in the 500 mg group. No IGF-I variations were seen between responsive and unresponsive patients in either treatment group. Our results in the 500 mg group are close to those obtained with aminoglutethimide and seem to agree with the hypothesis of an oestrogen-induced suppression of IGF-I circulating levels.
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  • 174
    ISSN: 1573-7217
    Keywords: breast cancer ; immunity ; tumor antigen ; ferritin ; iron ; transferrin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Fifty-two breast cancer patients were evaluated for levels of several molecules related to iron metabolism including determining their tumor tissue and serum ferritin levels, serum transferrin levels, and serum iron levels. In addition the patients' lymphocyte immunity against autologous tumor antigen was investigated. Forty percent (21 of 52) of the patients had lymphocyte immunity against tumor antigen. Iron metabolism molecules were expressed in abnormal quantities in some breast cancer patients: 27% (13 of 49) had elevated tumor tissue ferritin levels, 4% (2 of 49) had abnormally high serum ferritin, 10% (5 of 49) had abnormally low serum transferrin levels, and 43% (21 of 49) had depressed serum iron levels. None of these abnormalities in iron metabolism are associated with tumor immunity. These iron metabolism molecules may be indicative of rates of cell proliferation or may influence growth of breast cancer cells, but do not appear to influence host lymphocyte immunity against tumor associated antigens.
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  • 175
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    Breast cancer research and treatment 31 (1994), S. 325-335 
    ISSN: 1573-7217
    Keywords: breast cancer ; vimentin ; invasion ; integrins ; cadherins ; epithelial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Eighteen breast cancer cell lines were examined for expression of markers of epithelial and fibroblastic differentiation: E-cadherin, desmoplakins, ZO-1, vimentin, keratin and β1 and β4 integrins. The cell lines were distributed along a spectrum of differentiation from epithelial to fibroblastic phenotypes. The most well-differentiated, epithelioid cell lines contained proteins characteristic of desmosomal, adherens and tight junctions, were adherent to one another on plastic and in the basement membrane matrix Matrigel and were keratin-positive and vimentin-negative. These cell lines were all weakly invasive in anin vitro chemoinvasion assay. The most poorly-differentiated, fibroblastic cell lines were E-cadherin-, desmoplakin- and ZO-1-negative and formed branching structures in Matrigel. They were vimentin-positive, contained only low levels of keratins and were highly invasive in thein vitro chemoinvasion assay. Of all of the markers analyzed, vimentin expression correlated best within vitro invasive ability and fibroblastic differentiation. In a cell line with unstable expression of vimentin, T47DCO, the cells that were invasive were of the fibroblastic type. The differentiation markers described here may be useful for analysis of clinical specimens and could potentially provide a more precise measure of differentiation grade yielding more power for predicting prognosis.
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  • 176
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    Breast cancer research and treatment 32 (1994), S. 39-47 
    ISSN: 1573-7217
    Keywords: breast cancer ; p53 gene ; p53 protein ; prognosis ; therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Alterations of the p53 tumor suppressor gene are the most common genetic changes found so far in breast cancer, suggesting that the gene plays a central role in the development of the disease. p53 functions as a negative regulator of cell growth, and alterations in the gene lead to loss of this negative growth regulation and more rapid cell proliferation. A number of independent groups using different methods of detection have shown that p53 alterations are associated with more aggressive tumor biologic factors and a poorer prognosis in breast cancer patients. Because of its possible role in the regulation of apoptosis and response to DNA damage, p53 status could also be a predictive marker for response to hormonal or chemotherapy.
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  • 177
    ISSN: 1573-7217
    Keywords: antiestrogens ; breast cancer ; drug resistance ; flow cytometry ; tamoxifen ; toremifene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Flow cytometric analysis of DNA ploidy and S-phase fraction are well recognized prognostic indicators in breast cancer. The present paper deals with the widening of the applications of flow cytometry to monitoring the effectiveness of antiestrogen therapy, detecting clonal selection and emergence of drug resistance, and monitoring chemosensitizing properties of drugs. Antiestrogen activity can be studied by DNA flow cytometry to address clinical research problems such as patient-specific pharmacokinetics, dosing compliance, and acquired antiestrogen resistance. Patient plasma specimens containing various concentrations of triphenylethylenes can be monitored for drug-induced effects using cell cycle measurements and correlated toin vivo drug levels. DNA flow cytometry has also been instrumental in the study of the effects of prolonged low-dose (0.5 µM for 〉 100 days) tamoxifen treatment on human estrogen receptor negative MDA-MB-231 cells, where it was shown that tamoxifen may significantly alter cell cycle kinetics and tumorigenicity of these cells, selecting a new, more aggressive, and rapidly growing clone. Lastly, it has been shown that the chemosensitizing properties of another triphenylethylene antiestrogen, toremifene, on estrogen receptor negative, multidrug resistant MDA-MB-231-A1 human breast cancer cells can be studied using flow cytometric analysis. Toremifene (and its metabolites N-desmethyltoremifene and toremifene IV) are able to “resensitize” MDA-MB-231-A1 cells to vinblastine and doxorubicin, as reflected in a marked shift of cells to G2/M phase of the cell cycle. Flow cytometry is a widely available technique that might be applied clinically to monitor, at the cellular level, drug effects on tumors, including the modulators of drug resistance.
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  • 178
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    Breast cancer research and treatment 32 (1994), S. 73-84 
    ISSN: 1573-7217
    Keywords: bisphosphonates ; bone resorption ; breast cancer ; cadherins ; matrix metalloproteinases ; osteoclasts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Metastasis of breast cancer cells to bone consists of multiple sequential steps. To accomplish the process of metastasis to bone, breast cancer cells are required to intrinsically possess or acquire the capacities that are necessary for them to proliferate, invade, migrate, survive, and ultimately arrest in bone. These capacities are essential for any cancer cells to develop distant metastases in organs such as lungs and liver as well as bone. Once breast cancer cells arrest in bone, bone is a storehouse of a variety of cytokines and growth factors and thus provides an extremely fertile environment for the cells to grow. However, breast cancer cells are unable to progress in bone unless they destroy bone with the assistance of bone-resorbing osteoclasts. Thus, the capacity of breast cancer cells to collaborate with osteoclasts is likely to be specific and is likely critical for them to cause osteolytic bone metastases. Evidence to support the concept that there is an intimate relationship between breast cancer cells and osteoclasts is described using anin vivo bone metastasis model in which human breast cancer cells are inoculated into the left ventricle of nude mice. The roles of cell adhesion molecules including cadherins and laminin and matrix metalloproteinases in the development of osteolytic bone metastases by breast cancer are also discussed.
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  • 179
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    Breast cancer research and treatment 32 (1994), S. 97-103 
    ISSN: 1573-7217
    Keywords: breast cancer ; epidermal growth factor receptor ; immunotoxins ; ligand fusion toxins ; targeted therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Immunotoxins are a relatively new class of cytotoxic agents consisting of a catalytic toxin linked to an appropriate targeting ligand. The ligand directs the toxin to the surface of a tumor cell, whereupon the toxin enters the cell and catalytically inactivates the ribosome, thus disrupting protein synthesis and effecting cell death. Monoclonal antibodies (or their fragments) have been most commonly used to carry chemically conjugated toxins to proteins or antigens overexposed on the tumor cell surface, but specific ligands for tumor cell surface receptors could also provide effective targeting. The receptor for epidermal growth factor (EGFR) is overexpressed primarily in poor prognosis breast cancers that do not respond well to traditional therapies. Because EGFR is frequently overexpressed in breast cancer tissue and is associated with a poor prognosis, it is an attractive target for antitumor therapy. DAB 389 EGF is an EGFR specific fusion toxin produced with recombinant DNA techniques consisting of sequences for the enzymatically active and membrane translocation domains of diphtheria toxin plus sequences for human epidermal growth factor. DAB 389 EGF is a potent, EGFR specific, cytotoxic agent which rapidly inhibits protein synthesis by a mechanism of action similar to that of diphtheria itself. Preclinical studies in the laboratory and in animals now suggest the feasibility of investigating such an agent in the targeted therapy of patients with human breast cancer.
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  • 180
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    Breast cancer research and treatment 32 (1994), S. 113-118 
    ISSN: 1573-7217
    Keywords: axillary nodal status ; breast cancer ; neural networks ; prognostic markers ; staging ; survival analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Neural networks can be used as pattern recognition systems in complex data sets. We are exploring their utility in performing survival analysis to predict time to relapse or death. This technique has the potential to find easily some types of very complex interactions in data that would not be easily recognized by conventional statistical methods. In this paper we demonstrate that there are several ways neural networks can be used to find three-way interactions among variables. Thus, in data sets where such complex interactions exist, neural networks may find utility in detecting such interactions and in helping to produce predictive models.
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  • 181
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    Breast cancer research and treatment 32 (1994), S. 319-325 
    ISSN: 1573-7217
    Keywords: breast cancer ; computer modeling ; kinetics ; therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Since adjuvant chemotherapy and hormonal therapy generally extend disease free survival in breast cancer rather than provide a cure, we have examined the current breast cancer paradigm. Heterogeneity is a fundamental characteristic of breast cancer tissue and a well recognized aspect of the disease. There are variations in natural history, histopathology, biochemistry and endocrinology, and molecular biology of cancer tissues and cells within the tissues. A variety of data indicate that growth kinetics are also variable, not only from tumor to tumor, but also during the natural history of an individual's tumor. To better understand kinetic heterogeneity, a stochastic numeric computer model of the natural history of breast cancer has been developed. To be consistent with inter- and intratumor kinetic heterogeneity and with late relapse, the model predicts that tumors grow in an irregular fashion with alternating periods of growth and periods of dormancy rather than the generally accepted modified exponential, or Gompertzian fashion. The prediction of irregular growth has been compared to data relevant to growth characteristics of human breast cancer. Much data support the concept of irregular kinetics and temporary dormancy rather than steady, Gompertzian growth of human breast cancer. Thus, in addition to drug resistance, kinetic heterogeneity may help explain the limited impact that traditional chemotherapeutic treatment has had on mortality from breast cancer. Although the mechanisms underlying irregular growth need to be better understood, non-Gompertzian growth kinetics indicates that there may be alternative approaches for breast cancer treatment.
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  • 182
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    Breast cancer research and treatment 31 (1994), S. 61-71 
    ISSN: 1573-7217
    Keywords: antiestrogens ; breast cancer ; endometrium ; growth factors ; IGFs ; TGFs ; tamoxifen ; uterine cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The basis of the anti-proliferative action of antiestrogens is generally considered to be their ability to inhibit estrogen induced growth pathways by competitively inhibiting the binding of estrogen to the estrogen receptor. Recent data suggest that this may not be the entire story. Moreover, the cascade of events responsible for inhibition of mitogenesis after an initial interaction with the estrogen receptor is poorly understood. Multiple growth factor pathways operate in both normal and neoplastic estrogen/antiestrogen target tissues. While it is unlikely that any single pathway is pivotal, interactions of estrogen and/or antiestrogens with some of these pathways have been implicated in their proliferative effects. The exact molecular mechanisms remain unclear but autocrine, paracrine/juxtacrine, intracrine, and endocrine mediators or various combinations of them are likely to be involvedin vivo. Super-imposed on this is the possibility that ‘cross-talk’ between intracellular signaling pathways may also be involved. Elucidation of such molecular mechanisms will be important with respect to design of novel antiestrogenic/antimitogenic drugs and alternative treatment strategies for both breast and uterine cancer.
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  • 183
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    Breast cancer research and treatment 32 (1994), S. 1-4 
    ISSN: 1573-7217
    Keywords: breast cancer ; drug resistance ; growth factors ; heat shock proteins ; imaging ; premalignant disease ; prognostic factors ; tumor suppressor genes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
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  • 184
    ISSN: 1573-7217
    Keywords: breast cancer ; epidermal growth factor receptor ; immunocytochemistry ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Epidermal growth factor receptor (EGFR) is a potentially useful new biological prognostic and predictive indicator in human breast cancer. Additional research on EGFR is warranted to enhance our information on: i) the method of choice for its detection and quality control issues; ii) its association with novel pathobiological markers of prognosis; iii) its prognostic value in multivariate analysis; and iv) its capability to predict response to hormone therapy and, in the future, to biological treatments using antibodies against the specific receptor or its ligands. In the present study we update previous data on EGFR status, determined immunocytochemically, by prolonging the period of observation up to 5 years and by including, in the multivariate analysis, several new biological indicators. The main results obtained are: i) EGFR is weakly associated with Ki-67 score (p=0.073) and with p53 expression (p=0.06); ii) EGFR is a significant indicator for recurrence (p〈0.01 and odds ratio of 2.82) but not for death (p=0.27 and odds ratio of 1.49); iii) the prognostic power of EGFR is enhanced when combined with the knowledge of S-phase fraction; and iv) in multivariate analysis on relapse-free survival, EGFR and S-phase fraction (likelihood ratio test=26.40; p〈0.01), c-erbB-2 protein and p53 mutant protein expression (likelihood ratio test= 5.94; p=0.05), cathepsin D (likelihood ratio test= 9.78; p〈0.01), and nodal status (likelihood ratio test= 7.32; p〈0.01) are significant and independent prognostic factors in early-stage breast carcinoma. This new information could be of help for a more rational approach in the use of EGFR as a marker in future clinical research.
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  • 185
    ISSN: 1573-7217
    Keywords: breast cancer ; CAM 5.2 antibody ; cytokeratin ; flow cytometry ; prognosis ; S-phase fraction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Estimation of S-phase fraction in breast carcinomas with single parameter flow cytometry may include errors due to dilution of cancer cells by host cells. Use of tissue specific markers may to some extent correct for the effect of dilution. S-phase fraction was estimated by flow cytometry with and without immunoselection in 80 DNA-euploid breast carcinomas in stage I-II. The tumor tissue was mechanically disintegrated and fixed in ethanol. A primary antibody, specific for cytokeratins 8 and 18, was added before incubation with the secondary FITC-conjugated antibody. S-phase fraction was calculated for both the gated (cytokeratin-positive) and the ungated cell population. An increasing proportion of tetraploid cells compared to diploid cells was found when the immunoselection method was used. The gated population tended to have a higher S-phase fraction than the ungated population. In univariate analysis S-phase fraction estimated from both ungated and gated cell populations yielded significant information for predicting recurrence when stratified for tumor size and nodal status. In bivariate analysis S-phase fraction of the gated population contributed prognostic information in addition to S-phase fraction of the ungated population when both variables were included in the analysis. Our conclusion is that S-phase fraction calculated from cytokeratin-positive cells provides prognostic information in addition to ungated S-phase values in DNA euploid breast carcinomas.
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  • 186
    ISSN: 1573-7217
    Keywords: epidermal growth factor receptor ; breast cancer ; prognostic factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The prognostic value of epidermal growth factor receptor (EGF-R) was prospectively assessed in a series of 229 clinical T1-T2, N0-N1 breast carcinomas diagnosed between May 1987 and October 1989. EGF-R expression was determined by measuring the specific Bmax of125I EGF to tumor plasma membrane preparations. Tumor with a B max ≥ 3 fmol/mg of protein were considered positive with regard to EGF-R expression. With a median follow-up of 34 months, the 3-year overall and disease-free survivals are respectively 92% and 88% for EGF-R ≤ 3, and 91% and 86% EGF-R 〉 3 fmol, showing no significant difference, even when comparing axillary lymph node status. We did not succeed in finding an EGF-R cut-off value which might be significant in univariate analysis. Multivariate analysis of our data indicates that pT (p = 0.001), pN (p = 0.04), and Scarff-Bloom grade (p = 0.04) are the only significant predictors of disease-free survival among the parameters investigated in this study.
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  • 187
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    Breast cancer research and treatment 30 (1994), S. 81-87 
    ISSN: 1573-7217
    Keywords: 4-hydroxyandrostenedione ; aromatase ; aromatase inhibitor ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 4-hydroxyandrostenedione is a steroidal, suicide substrate inhibitor of aromatase, which has been widely tested in postmenopausal breast cancer patients. It is highly specific with the only notable endocrine changes other than oestrogen suppression being a dose-related suppression of sex-hormone binding globulin when the drug is given orally (a reflection of the drug's minor androgenic activity). Intramuscular administration of 250 mg every second week is the schedule of choice. This achieves peripheral aromatase inhibition of about 85% and oestradiol suppression of about 65%. The drug is usually used second-line, after tamoxifen, with an overall response rate in unselected patients of 26%. Side-effects are minimal and consist almost entirely of local reactions at the site of injection. 4-hydroxyandrostenedione is therefore a useful new treatment option as the first selective aromatase inhibitor to have wide clinical availability.
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  • 188
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    Breast cancer research and treatment 30 (1994), S. 95-102 
    ISSN: 1573-7217
    Keywords: breast cancer ; aromatase inhibitors ; CGS 20267 ; CGS 16949A ; hormone ablative therapy ; breast cancer treatment ; endocrine therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Fadrozole Hydrochloride (CGS 16949A) and Letrozole (CGS 20267), are two of the newest non-steroidal, orally active aromatase inhibitors currently being evaluated as second line treatment of patients with hormone dependent forms of metastatic breast cancer. In a phase I clinical efficacy study, we examined the ability of these two imidazole derivatives to suppress the synthesis of estrogen in a cohort of postmenopausal patients with metastatic breast cancer. Both medications at relatively low doses were potent and rapid inhibitors of aromatase activity as evidenced by their ability to suppress the level of blood and urine estradiol and estrone as well as blood estrone sulfate in these patients. Letrozole appeared to be the more potent of the two, with over 95% suppression of both plasma and urinary estrogens observed within 2 weeks of therapy. Letrozole appeared to be more selective than Fadrozole in inhibiting aromatase activity in that no compromise in cortisol and aldosterone output was evident with Letrozole therapy at all of the doses tested, a compromise clearly seen with Fadrozole. The inhibition of aromatase activity by these imidazole derivatives as second line therapy for patients with hormone dependent breast cancer appears to be a favorable alternative form of hormone ablative therapy and holds considerable promise for the treatment of this malignancy.
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  • 189
    ISSN: 1573-7217
    Keywords: malignant progression ; estrogen ; carcinogenesis ; hormone dependence ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have established and characterized a series of variant cell lines in which to identify the critical factors associated with E2-induced malignant progression, and the acquisition to tamoxifen resistance in human breast cancer. Sublines of the hormone-dependent MCF-7 cell line (MCF7/MIII and MCF7/LCC1) form stable, invasive, estrogen independent tumors in the mammary fat pads of ovariectomized athymic nude mice. These cells retain expression of both estrogen (ER) and progesterone receptors (PGR), but retain sensitivity to each of the major structural classes of antiestrogens. The tamoxifen-resistant MCF7/LCC2 cells retain sensitivity to the inhibitory effects of the steroidal antiestrogen ICI 182780. By comparing the parental hormone-dependent and variant hormone-independent cells, we have demonstrated an altered expression of some estrogen regulated genes (PGR, pS2, cathepsin D) in the hormone-independent variants. Other genes remain normally estrogen regulated (ER, laminin receptor, EGF-receptor). These data strongly implicate the altered regulation of a specific subset or network of estrogen regulated genes in the malignant progression of human breast cancer. Some of the primary response genes in this network may exhibit dose-response and induction kinetics similar to pS2, which is constitutively upregulated in the MCF7/MIII, MCF7/LCC1 and MCF7/LCC2 cells.
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  • 190
    ISSN: 1573-7217
    Keywords: stromal epithelial interactions ; insuline-like growth factors ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The prominent ‘desmoplastic’ or stromal reaction seen in many invasive breast carcinomas lead to early speculation that stromal cells play a role in breast cancer pathogenesis [1]. Experimental evidence now supports this hypothesis and interactions between stromal cells and epithelial cells appear to be important for both normal mammary development and neoplasia. The identification of genes that are selectively expressed in the stroma of malignant breast lesions has recently provided new insights into the molecular basis of stromal-epithelial interactions. Stromally expressed genes include growth factors, proteases and extracellular matrix proteins, all biological activities with potential roles in malignant progression. Investigations discussed here concern the nature of the paracrine signals provided by malignant epithelial cells that activate changes in stromal gene expression, the effect that the stromally derived factors have on the behavior of malignant epithelial cells and the identification of novel factors and receptors in either stroma or epithelia that contribute to their mutual interactions. These questions will be addressed in the context of this laboratory's studies on insulin-like growth factors, as these molecules show marked differences in stromal expression between benign and malignant breast tissue and thus provide a useful paradigm for investigations into the paracrine environment of an evolving breast tumor.
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  • 191
    ISSN: 1573-7217
    Keywords: breast cancer ; oncogenes ; p53 transformation ; temperature sensitive mutant ; tumor suppressors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary One common step in the malignant progression of a wide variety of human cancers seems to be inactivation of the p53 gene, via point mutation or deletion or both; or overexpression of mutated protein with dominant transforming activity. This study shows a suppressive effect of wild type p53 on the growth of human breast cancer cells. Introduction of wild type p53 versus mutant into five human breast cancer cell lines containing mutant p53 resulted in a marked reduction in colony formation. Two of these were transfected with human wt p53 expression vectors and the other three were infected with retroviruses packaging human wt p53, both showing similar reduction in the number of surviving colonies, suggesting a role for wt p53 in suppression of breast cancer cell growth. Direct evidence for growth suppression was obtained by introduction of the temperature sensitive p53Val135 into Hs578T human breast cancer cells containing a mutant p53. This murine mutant allele p53Val135 functions as an oncogene at 37° C and as a tumor suppressor at 32° C. The cell line generated was strongly growth inhibited at the restrictive temperature (31.5° C), at which temperature the suppressor form is expressed. This inhibition of proliferation was reversible upon a temperature upshift. Analysis of the cell cycle distribution shows these growth suppressed cells to be inhibited in the G1 phase of the cell cycle. Thus wt p53 may have an important role in breast cancer tumorigenesis.
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  • 192
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    Breast cancer research and treatment 30 (1994), S. 197-200 
    ISSN: 1573-7217
    Keywords: breast cancer ; CA 15-3 ; IAP ; immunosuppressive acidic protein ; tumor markers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Immunosuppressive acidic protein (IAP) has been described as a tumor marker in a number of malignant diseases. To evaluate the clinical importance of IAP in breast cancer patients, IAP serum level was determined in 75 breast cancer patients, using single radial immunodiffusion. Serum samples were also tested for CA 15-3. Cut off value for IAP was determined according to IAP serum level in 50 patients with benign, non inflammatory, diseases, and was set as 725 microgram/ml. Mean IAP serum level (623 mcg/ml) and positivity rate (20%) in 24 breast cancer patients with active disease were similar to those in 51 breast cancer patients with no evidence of disease (590 mcg/ml and 18%). The mean CA 15-3 serum level and positivity rate were significantly higher in patients with active disease (200 units/ml, 67%), compared to patients with no evidence of disease (18.3 units/ml, 6%). In our experience IAP was not found to be an effective tumor marker in breast cancer.
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  • 193
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    Breast cancer research and treatment 30 (1994), S. 201-204 
    ISSN: 1573-7217
    Keywords: breast cancer ; hepatocellular carcinoma ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It has been hypothesized that hepatocellular carcinoma might be a long-term adverse effect of tamoxifen therapy. Data from nine population-based cancer registries in the United States were used to investigate time trends in the incidence of hepatocellular carcinoma in white women previously diagnosed with invasive breast cancer during 1974–1987 and followed until 1989. Of particular interest were the rates after 1977, the year tamoxifen was licensed by the FDA. Compared to rates in all white women, no increased risk of hepatocellular carcinoma was found in women most likely to have received tamoxifen - those 50 years of age or more at diagnosis of breast cancer and diagnosed after 1977. These results suggest that tamoxifen does not cause a large increase in the incidence of hepatocellular carcinoma within the first decade after use. However, smaller and/or later increases in the risk for hepatocellular carcinoma are possible and warrant continued monitoring of women treated with tamoxifen.
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  • 194
    ISSN: 1573-7217
    Keywords: breast cancer ; folinic acid ; 5FU ; metastatic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Standard combination chemotherapy for metastatic breast cancer produces response rates between 30–60% with limited impact on survival. We undertook a phase II trial to determine the activity of 5 fluorouracil (5FU) and folinic acid (FA) in patients with measurable metastatic or recurrent breast cancer who had received no prior chemotherapy. Patients meeting the eligibility criteria received 5FU 370 mg/m2/day and FA 200 mg/m2/day for 5 days repeated every 28 days, toxicity allowing. Response defined by standard criteria was assessed every 8 weeks and toxicity according to WHO criteria was determined on every course. Thirty-three patients were entered on trial. Thirty-two patients were evaluable for response and 33 for toxicity. The dose limiting toxicity was stomatitis with 7/32, 19/32, and 5/32 patients experiencing grade 1, 2, and 3 toxicity. Grades 1 and 2 diarrhea occurred in 17/32 and 11/32 patients respectively. Myelosuppression was not significant. Two complete and 11 partial responses were observed. The overall response rate was 41% (95% CI, 24–58%). Responses were seen in soft tissue and visceral sites. Patients who had received adjuvant chemotherapy more than 6 months prior to receiving 5FU and FA responded also. Six of 29 patients receiving standard combination chemotherapy as second line treatment responded subsequently. We concluded: 1) 5FU and FA is an active combination in the treatment of breast cancer warranting further evaluation in combination with other drugs; 2) the dose-limiting toxicity of stomatitis is tolerable; 3) patients receiving 5FU and FA as first line therapy can respond to conventional combination chemotherapy as second line treatment.
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  • 195
    ISSN: 1573-7217
    Keywords: breast cancer ; monoclonal antibodies ; mucins ; multivariate analysis ; prognosis ; relapse ; survival
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Monoclonal antibody (MoAb) BrE-3, an anti-human milk fat globule (HMFG) MoAb, is used here as a novel prognostic indicator for survival and relapse time in patients with infiltrating ductal carcinoma of the breast. A scoring system (4-Score method) was developed to this effect that measured, in a statistically reliable fashion, the level of expression of the epitope for MoAb BrE-3 in the cytoplasm and membranes of breast carcinoma cells in paraffin-embedded sections. In univariate analysis, data obtained by the 4-Score Method as well as data from traditional prognostic indicators (tumor size, axillary node status, and grade of differentiation) were found to be associated with patient survival and relapse. In multivariate analysis, using a Cox proportional hazards regression model, levels of expression of BrE-3 epitope plus tumor size and axillary node status were weighted and combined in an Individual Linear Composite Prognostic Score (ILCPS) that had a high level of association with survival and relapse time in this sample model of patients with infiltrating ductal carcinoma of the breast. This level of association was found to be higher than the level of association for any other combination of traditional or 4-Score method variables. The level of expression of BrE-3 significantly adds to the prognostic capacity of traditional prognostic markers for infiltrating ductal carcinoma of the breast.
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  • 196
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    Breast cancer research and treatment 30 (1994), S. 283-292 
    ISSN: 1573-7217
    Keywords: breast cancer ; oral contraceptives ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In 471 breast cancer patients the influence of a positive history of oral contraceptive (OC) use on survival was investigated. 297 (63%) patients used OCs during any period of their life and 92 (20%) used them still at the time of diagnosis. Sixty months after diagnosis OC users had a significantly increased overall survival (p = 0.037). Survival rates amounted to 79.5% and 70.3% for OC users and non-users, respectively. The effect persisted after adjustment for other prognostic factors and was mainly attributed to women who had taken OCs four years or longer (p = 0.025). Comparing the survival after a 56 months median follow-up dependent on duration of OC use (never, 1–48 months, ≥ 49 months) in subgroups of prognostic factors, the most significant influence on survival was observed among long-term users with tumors more than 2 cm in diameter (p = 0.005), with axillary node-positive tumors (1–3 nodes, p = 0.055/≥ 4 nodes, p = 0.019), and with tumors of low estrogen receptor (p = 0.015) or progesterone receptor content (p = 0.04). The difference in survival between OC users and non-users cannot be explained by the distribution of prognostic factors investigated (histological type, histological grade, tumor size, lymph node involvement, hormonal receptor content). OC users had an even higher percentage of poorly differentiated tumors (p = 0.003). These results suggest an effect of OC use on tumor biology during the preclinical phase of the disease.
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  • 197
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    Breast cancer research and treatment 31 (1994), S. 27-39 
    ISSN: 1573-7217
    Keywords: antiestrogen ; breast cancer ; endometrial carcinoma ; endometrium ; tamoxifen ; uterus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Since its introduction in the early seventies, the list of indications for the use of the antiestrogen tamoxifen has been continuously expanded. Tamoxifen is now used for the treatment of metastatic breast cancer and for long-term and often indefinite administration as an adjuvant therapy. Large clinical trials in three countries are now evaluating the efficacy of tamoxifen as a preventive agent. However, tamoxifen therapy has been associated with an increased incidence of endometrial carcinoma. Laboratory and clinical data available to date on this controversial issue can be summarized as follows: a) Tamoxifen can have an estrogenic effect on endometrium in the presence of low estrogen levels. b) Tamoxifen treatment is probably associated with an increased incidence of endometrial cancer; however, this association appears to be linked to higher tamoxifen doses (40mg/d). d) It is not known whether tamoxifen causes or allows the identification of occult endometrial carcinoma. e) At the present time there is evidence for a tumor promoting effect of tamoxifen on endometrial cancer at a dose of 20 mg per day. f) Replacement of tamoxifen by ‘pure’ antiestrogens or coadministration of progestins with tamoxifen do not appear to offer benefit unless clinical trials demonstrate a reduced incidence of endometrial problems. g) Patientsmust be evaluated for pre-exsisting endometrical carcinoma before starting tamoxifen therapy. f) Close followup of long-term tamoxifen patients with endometrial biopsies is recommended with individuals who experience symptoms.
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  • 198
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    Breast cancer research and treatment 31 (1994), S. 41-52 
    ISSN: 1573-7217
    Keywords: tamoxifen ; pure antiestrogens ; breast cancer ; prevention ; resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The success of antiestrogen therapy to treat all stages of breast cancer, and the evaluation of tamoxifen as a preventive for breast cancer in normal women, have focused attention on the molecular mechanisms of antiestrogen action and mechanisms of drug resistance. The overall goal of research is to enhance current therapies and to develop new approaches for breast cancer treatment and prevention. Recent studies show that tamoxifen and the new pure antiestrogens appear to have different mechanisms of action: tamoxifen and related compounds cause a change in the folding of the steroid binding domain that prevents gene activation whereas the pure antiestrogens cause a reduced interaction at response elements and cause a rapid loss of receptor complexes. Tamoxifen treatment produces changes in the cellular and circulating levels of growth factors that could influence both receptor negative or receptor positive tumor growth and the metastatic potential of a tumor. These events may explain the survival advantage observed with tamoxifen therapy. However, the current therapeutic challenge is to avoid drug resistance during long-term tamoxifen therapy. Numerous explanations for drug resistance to tamoxifen have been suggested, including elevated estrogen levels, increased tumor antiestrogen binding sites, receptor mutations, and impaired signal transduction. However, it is probable that multiple mechanisms evolve to facilitate tumor survival. Most importantly, current research is examining mechanisms responsible for the beneficial actions of tamoxifen on bones and lipids as well as the potentially deleterious effects of tamoxifen on liver and endometrial carcinogenesis and retinopathy. The urgent need to understand antiestrogenic drug mechanisms and toxicity is being facilitated by the application of the technology developed for basic molecular biology.
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  • 199
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    Breast cancer research and treatment 31 (1994), S. 263-271 
    ISSN: 1573-7217
    Keywords: MDR1 ; Sp1 ; p53 ; PKA ; 8-Cl-cAMP ; breast cancer ; multidrug resistance ; transcription
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The development of cross-resistance to many natural product anticancer drugs, termed multidrug resistance (MDR), is one of the major reasons why cancer chemotherapy ultimately fails. This type of MDR is often associated with over-expression of theMDR1 gene product, P-glycoprotein (Pgp), a multifunctional drug transporter. The expression of MDR in breast tumors is related to their origination from a tissue that constitutively expresses Pgp as well as to the development of resistance during successive courses of chemotherapy. Therefore, understanding the mechanisms that regulate the transcriptional activation ofMDR1 may afford a means of reducing or eliminating MDR. We have found thatMDR1 expression can be modulated by type I cAMP-dependent protein kinase (PKA), opening up the possibility of modulating MDR by selectively down-regulating the activity of PKA-dependent transcription factors which upregulateMDR1 expression. High levels of type I PKA occurs in primary breast carcinomas and patients exhibiting this phenotype show decreased survival. The selective type I cAMP-dependent protein kinase (PKA) inhibitors, 8-Cl-cAMP and Rp8-Cl-cAMP[S] may be particularly useful for downregulating PKA-dependent MDR-associated transcription factors, and we have found these compounds to downregulate transient expression of a reporter gene under the control of severalMDR1 promoter elements. Thus, investigations of this nature should not only lead to a greater understanding of the mechanisms governing the expression of MDR, but also provide a focus for pharmacologic intervention by a new class of inhibitors.
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  • 200
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    Breast cancer research and treatment 31 (1994), S. 301-307 
    ISSN: 1573-7217
    Keywords: breast cancer ; tamoxifen ; estrogen receptor ; antiestrogen resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Acquisition of the antiestrogen resistance by breast cancer cellsin vivo may result from a variety of mechanisms. The main pathway appears to involve loss of estrogen receptor (ER) expression or selection for ER negative cells among heterogenous population of tumor cells. However, clinical data suggest that, in about 30% of the cases, antiestrogen resistance arises even in the presence of estrogen receptors. Postulated mechanisms leading to the latter phenotype include selection for variant receptor forms during treatment, development of novel metabolic pathways for the drug, loss of nuclear co-factors, or activation of signal transduction pathway that cross activate ER signals. We have used anin vitro experimental system utilizing LY-2 cell line, an ER positive and antiestrogen resistant MCF-7 cell variant, to study the mechanism of antiestrogen resistance in the presence of functional ER. Result from a complementation experiment suggests that LY-2 phenotype is a recessive trait. Cloning of the genetic defect in the LY-2 cells would provide further insight for the mechanism of antiestrogen resistance in ER positive breast cancer cells.
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