Skip to main content
SpringerLink
Log in

Cathepsin D expression by cancer and stromal cells in breast cancer: an immunohistochemical study of 1348 cases

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

This study was aimed at investigating the influence of cathepsin D (CD) expression by cancer cells and stromal cells on breast cancer prognosis. This is a study of 1348 node‐positive (NPBC) and node‐negative (NNBC) breast cancers diagnosed between 1980 and 1986 and with a minimum follow‐up of 5.2 years. CD expression was assessed by immunohistochemistry on archival material using a polyclonal antibody. The expression by cancer and stromal cells was assessed separately and correlated with distant metastasis free (DMFS) and overall survival (OS). Cancer cells expressed CD (more than 10% cells expressing CD) in 38.9% of cases and reactive stromal cells in 43.6%. CD expression by reactive stromal cells, and not cancer cells, correlated with several factors of poor prognosis by cancer cells. A strong association was also found with expression of other proteases (stromelysin‐3, gelatinase A, and urokinase Plasminogen Activator) by these same reactive stromal cells. CD expression by cancer cells did not predict DMFS or OS but, by univariate analysis, CD expression by reactive stromal cells was associated with earlier recurrence and shorter survival in NNBC (p = 0.0425) and NPBC patients submitted to adjuvant chemotherapy (p = 0.0234). However, CD expression by reactive stromal cells remained a significant predictor of recurrence by multivariate analyses only in a subgroup of NPBC submitted to adjuvant chemotherapy. Overall, those data support the concept that proteases produced by reactive stromal cells are under cancer cell stimulation and that CD by stromal cells, and not cancer cells, influences the prognosis, but only in a subgroup of patients with breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ferrandina G, Scambia G, Bardelli F, Benedetti Panici P, Mancuso S, Messori A: Relationship between cathepsin-D content and disease-free survival in node-negative breast cancer patients: a meta-analysis. Br J Cancer 76: 661–666, 1997

    Google Scholar 

  2. Isola J, Weitz S, Visakorpi T, Holli K, Shea R, Khabbaz N, Kallioniemi OP: Cathepsin D expression detected by immunohistochemistry has independent prognostic value in axillary node-negative breast cancer. J Clin Oncol 11: 36–43, 1993

    Google Scholar 

  3. Lösch A, Tempfer C, Kohlberger P, Joura EA, Denk M, Zajic B, Breitenecker G, Kainz C: Prognostic value of cathepsin D expression and association with histomorphological subtypes in breast cancer. Br J Cancer 78: 205–209, 1998

    Google Scholar 

  4. Domagala W, Striker G, Szadowska A, Dukowicz A, Weber K, Osborn M: Cathepsin D in invasive ductal NOS breast carcinoma as defined by immunohistochemistry. No correlation with survival at 5 years. Am J Pathol 141: 1003–1012, 1992

    Google Scholar 

  5. Kandalaft PL, Chang KL, Ahn CW, Traweek ST, Mehta P, Battifora H: Prognostic significance of immunohistochemical analysis of cathepsin D in low-stage breast cancer. Cancer 71: 2756–2763, 1993

    Google Scholar 

  6. Henry JA, McCarthy AL, Angus B, Westley BR, May FEB, Nicholson S, Cairns J, Harris AL, Home CHW: Prognostic significance of the estrogen-regulated protein, cathepsin D, in breast cancer: an immunohistochemical study. Cancer 65: 265–271, 1990

    Google Scholar 

  7. Têtu B, Brisson J, Côté C, Brisson S, Potvin D, Roberge N: Prognostic significance of cathepsin D expression in nodepositive breast carcinoma: an immunohistochemical study. Int J Cancer 55: 429–435, 1993

    Google Scholar 

  8. Joensuu H, Toikkanen S, Isola J: Stromal cell cathepsin D expression and long-term survival in breast cancer. Br J Cancer 71: 156–159, 1995

    Google Scholar 

  9. Nadji M, Fresno M, Nassiri M, Conner G, Herrero A, Morales AR: Cathepsin D in host stromal cells, but not in tumor cells, is associated with aggressive behavior in node-negative breast cancer. Hum Pathol 27: 890–895, 1996

    Google Scholar 

  10. O'Donoghue AEMA, Poller DN, Bell JA, Galea MH, Elston CW, Blamey RW, Ellis IO: Cathepsin D in primary breast carcinoma: adverse prognosis is associated with expression of cathepsin D in stromal cells. Breast Cancer Res Treat 33: 137–145, 1995

    Google Scholar 

  11. Hsu SM, Raine L, Fanger H: Use of avidin–biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29: 577–580, 1981

    Google Scholar 

  12. Dressler LG, Bartow SA: DNA flow cytometry in solid tumors: practical aspects and clinical applications. Sem Diagn Pathol 6: 55–82, 1989

    Google Scholar 

  13. Erdos T, Best-Belpomme M, Bessada R: A rapid assay for binding estradiol to uterine receptor(s). Anal Biochem 37: 244–252, 1970

    Google Scholar 

  14. Wolf C, Rouyer N, Lutz Y, Adida C, Loriot M, Bellocq JP, Chambon P, Basset P: Stromelysin-3 belongs to a subgroup of proteinases expressed in breast carcinoma fibroblastic cells and possibly implicated in tumor progression. Proc Natl Acad Sci USA 90: 1843–1847, 1993

    Google Scholar 

  15. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Amer Statist Assoc 53: 453–481, 1958

    Google Scholar 

  16. Armitage P: Statistical Methods in Medical Research. John Wiley & Sons, New York, 1991

    Google Scholar 

  17. Cox DR: Regression models and lifetables (with discussion). JR Statist Soc 34: 187–220, 1972

    Google Scholar 

  18. Ravdin PM, Tandon AK, Allred DC, Clark GM, Fuqua SA, Hilsenbeck SH, Chamness GC, Osborne CK: Cathepsin D by western blotting and immunohistochemistry: failure to confirm correlations with prognosis in node-negative breast cancer. J Clin Oncol 12: 467–474, 1994

    Google Scholar 

  19. Winstanley JH, Leinster SJ, Cooke TG, Westley BR, Platt HA, Rudland PS: Prognostic significance of cathepsin-D in patients with breast cancer. Br J Cancer 67: 767–772, 1993

    Google Scholar 

  20. Johnson MD, Tori JA, Lippman ME, Dickson RB: The role of cathepsin D in the invasiveness of human breast cancer cells. Cancer Res 53: 873–877, 1993

    Google Scholar 

  21. Tandon AK, Clark GM, Chamness GC, Chirgwin JM, McGuire WL: Cathepsin D and prognosis in breast cancer. N Engl J Med 322: 297–302, 1990

    Google Scholar 

  22. Duffy MJ, Brouillet JP, Reilly D, McDermott E, O'Higgins N, Fennelly JJ, Maudelonde T, Rochefort H: Cathepsin D concentration in breast cancer cytosols: correlation with biochemical, histological, and clinical findings. Clin Chem 37: 101–104, 1991

    Google Scholar 

  23. Romain S, Muracciole X, Varette I, Bressac C, Brandone H, Martin PM: La cathepsine D: un facteur pronostique indépendant dans le cancer du sein. Bull Cancer Paris 77: 439–447, 1990

    Google Scholar 

  24. Spyratos F, Maudelonde T, Brouillet JP, Brunet M, Defrenne A, Andrieu C, Hacene K, Desplaces A, Rouesse J, Rochefort H: Cathepsin D: an independent prognostic factor for metastasis of breast cancer. Lancet 2: 1115–1118, 1989

    Google Scholar 

  25. Razumovic JJ, Stojkovic RR, Petrovecki M, Gamulin S: Correlation of two methods for determination of cathepsin D in breast carcinoma (immunohistochemistry and ELISA in cytosol). Breast Cancer Res Treat 43: 117–122, 1997

    Google Scholar 

  26. Roger P, Montcourrier P, Maudelonde T, Brouillet JP, Pages A, Laffargue F, Rochefort H: Cathepsin D immunostaining in paraffin-embedded breast cancer cells and macrophages: correlation with cytosolic assay. Hum Pathol 25: 863–871, 1994

    Google Scholar 

  27. Charpin C, Devictor B, Bonnier P, Andrac L, Lavaut MN, Allasia C, Piana L: Cathepsin D immunocytochemical assays in breast carcinomas: image analysis and correlation to prognostic factors. J Pathol 170: 463–470, 1993

    Google Scholar 

  28. Ravdin PM, Chamness GC: The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers – a review. Gene 159: 19–27, 1995

    Google Scholar 

  29. Têtu B, Brisson J: Prognostic significance of HER-2/neu oncoprotein expression in node-positive breast cancer. The influence of the pattern of immunostaining and adjuvant therapy.Cancer 73: 2359–2365, 1994

    Google Scholar 

  30. Pupa SM, Bufalino R, Invernizzi AM, Andreola S, Rilke F, Lombardi L, Colnaghi MI, Menard S: Macrophage infiltrate and prognosis in c-erbB-2-overexpressing breast carcinomas. J Clin Oncol 14: 85–94, 1996

    Google Scholar 

  31. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL: Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56: 4625–4629, 1996

    Google Scholar 

  32. Noël AC, Polette M, Lewalle JM, Munaut C, Emonard HP, Birembaut P, Foidart JM: Coordinate enhancement of gelatinase A mRNA and activity levels in human fibroblasts in response to breast-adenocarcinoma cells. Int J Cancer 56: 331–336, 1994

    Google Scholar 

  33. Ito A, Nakajima S, Sasaguri Y, Nagase H, Mori Y: Co-culture of human breast adenocarcinoma MCF-7 cells and human dermal fibroblasts enhances the production of matrix metalloproteinases 1, 2 and 3 in fibroblasts. Br J Cancer 71: 1039–1045, 1995

    Google Scholar 

  34. Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H, Nabeshima K: The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 55: 434–439, 1995

    Google Scholar 

  35. Gasparini G, Harris L: Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. J Clin Oncol 13: 765–782, 1995

    Google Scholar 

  36. Weidner N, Semple JP, Welch WR, Folkman J: Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma. N Engl J Med 324: 1–8, 1991

    Google Scholar 

  37. Hildenbrand R, Dilger I, Horlin A, Stutte HJ: Urokinase plasminogen activator induces angiogenesis and tumor vessel invasion in breast cancer. Pathol Res Pract 191: 403–409, 1995

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Université Laval, Québec, Canada

    Bernard Têtu, Hélène Lapointe & Chang Shu Wang

  2. Groupe de Recherche en Épidémiologie, Université Laval, Québec, Canada

    Jacques Brisson, Pascale Bernard & Caty Blanchette

Authors
  1. Bernard Têtu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacques Brisson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hélène Lapointe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chang Shu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pascale Bernard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Caty Blanchette
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Têtu, B., Brisson, J., Lapointe, H. et al. Cathepsin D expression by cancer and stromal cells in breast cancer: an immunohistochemical study of 1348 cases. Breast Cancer Res Treat 55, 135–145 (1999). https://doi.org/10.1023/A:1006140213493

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006140213493

Search

Navigation