Skip to main content
SpringerLink
Log in

IGF-I and retinoic acid regulate the distribution pattern of IGFBPs synthesized by the canine mammary tumor cell line CMT-U335

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

Abstract

Stromal-epithelial interactions modulate growth and development in normal and neoplastic mammary gland. The release of IGF binding proteins (IGFBPs) by the stromal compartment of the mammary gland may play a modulating role in the IGF-mediated proliferation of mammary epithelium. Therefore, the IGFBP-expression pattern of the canine mammary tumor cell line U335 (CMT-U335), which has a mesenchymal phenotype, was determined. In addition, the effects of IGFs and all trans retinoic acid (RA) on DNA synthesis, and IGFBP secretion and distribution were examined. The IGFBPs secreted by CMT-U335 were characterized as IGFBP-2, -4, -5, and -6. Moreover, CMT-U335 appeared to be a suitable mammary mesenchymal cell line for study of the regulatory factors of IGFBP expression and the mechanism(s) involved. IGFs and RA enhanced IGFBP concentrations in cell-conditioned medium with IGF-I and RA having an additive effect. The IGF-I-stimulated DNA synthesis, however, was inhibited by RA. The difference between IGF-I and RA was an enhanced IGFBP-5 binding to the extracellular matrix (ECM) by RA, whereas IGF-I reduced binding to the ECM. Because high doses of insulin had no significant effects on IGFBP concentrations in the medium, it is concluded that IGF-I-induced changes in IGFBP concentrations are not mediated by type-I IGF receptors and may be the consequence of IGFBP redistribution.

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. Bostock DE: The prognosis following the surgical excision of canine mammary neoplasms. Eur J Cancer 11: 389–396, 1975

    Google Scholar 

  2. Owen LN, Briggs MH: Contraceptive steroid toxicology in the beagle dog and its relevance to human carcinogenecity. Curr Med Res Opin 4: 309–329, 1976

    Google Scholar 

  3. El Etreby MF, Gråf KJ: Effect of contraceptive steroids on mammary gland of female dog and its relevance to human carcinogenecity. Pharmacol Ther 5: 369–402, 1979

    Google Scholar 

  4. Casey HW, Giles RC, Kwapien RP: Mammary neoplasms in animals. Pathologic aspects and the effect of contraceptive steroids. Recent Results. Cancer Res 66: 129–160, 1979

    Google Scholar 

  5. Misdorp, W: Progestagens and mammary tumors in dogs and cats. Acta Endocrinol 125: 27–31, 1991

    Google Scholar 

  6. Rutteman GR: Contraceptive steroids and the mammary gland: Is there a hazard? Insights from animals studies. Breast Cancer Res Treat 23: 29–41, 1992

    Google Scholar 

  7. Concannon PW, Altszuler N, Hampshire J, Butler WB, Hansel W: Growth hormone, prolactin, and cortisol in dogs developing mammary nodules and an acromegalic-like appearance during treatment with medroxy-progesterone acetate. Endocrinology 106: 1173–1177, 1980

    Google Scholar 

  8. Rijnberk A, Eigenmann JE, Belshaw BE, Hampshire J, Altszuler N: Acromegaly associated with transient overproduction of growth hormone in a dog. J Am Vet Med Assoc 177: 534–537, 1980

    Google Scholar 

  9. Eigenmann JE, Rijnberk A: Influence of medroxyprogesterone acetate (Provera) on plasma growth hormone levels and on carbohydrate metabolism: I. Studies in the ovariohysterectomized bitch. Acta Endocrinol 98: 599–602, 1981

    Google Scholar 

  10. Selman PJ, Mol JA, Rutteman GR, Rijnberk A: Progestininduced growth hormone excess in the dog originates in the mammary gland. Endocrinology 134: 287–292, 1994

    Google Scholar 

  11. Mol JA, van Garderen E, Selman PJ, Wolfswinkel J, Rijnberk A, Rutteman GR: Growth Hormone mRNA in mammary gland tumors of dogs and cats. J Clin Invest 95: 2028–2034, 1995

    Google Scholar 

  12. Daughaday WH, Rotwein P: Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 10: 68–91, 1989

    Google Scholar 

  13. Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16: 3–35, 1995

    Google Scholar 

  14. Pekonen F, Nyman T, Ilvesmåki V, Partanen S: Insulinlike growth factor binding proteins in human breast cancer tissue. Cancer Res 52: 5204–5207, 1992

    Google Scholar 

  15. Figueroa JA, J ackson JG, McGuire WL, Krywicki RF, Yee, D: Expression of insulin-like growth factor binding proteins in human breast cancer correlates with estrogen receptor status. J Cell Biochem 52: 196–205, 1993

    Google Scholar 

  16. McGuire SE, Hilsenbeck SG, Figueroa JA, Jackson JG, Yee D: Detection of insulin-like growth factor binding proteins (IGFBPs) by ligand blotting in breast cancer tissues. Cancer Lett 77: 25–32, 1994

    Google Scholar 

  17. Clemmons DR, Camacho-Hübner C, Coronado E, Osborne CK: Insulin-like growth factor binding protein secretion by breast carcinoma cell lines: correlation with estrogen receptor status. Endocrinology 127: 2679–2686, 1990

    Google Scholar 

  18. Jetten AM: In: Guroff, G (ed) Growth and Maturation Factors. Vol 3. Wiley, New York, 1985, pp. 252–293

    Google Scholar 

  19. Fontana JA, Burroes-Mezu A, Clemmons DR, LeRoith D: Retinoid modulation of insulin-like growth factor binding proteins and inhibition of breast carcinoma proliferation. Endocrinology 127: 1115–1122, 1991

    Google Scholar 

  20. Adamo ML, Shao Z-M, Lanau F, Chen J-C, Clemmons DR, Roberts CT, LeRoith D, Fontana JA: Insulin-like growth factor-I (IGF-I) and retinoic acid modulation of IGF-binding proteins (IGFBPs): IGFBP-2,-3, and-4 gene expression and protein secretion in a breast cancer cell line. Endocrinology 131: 1859–1867, 1992

    Google Scholar 

  21. Sheikh MS, Shao Z-M, Hussain A, Clemmons DR, Chen J-C, Roberts CT, LeRoith D, Fontana JA: Regulation of insulin-like growth factor binding protein-1, 2, 3, 4, 5, and 6: synthesis, secretion, and gene expression in estrogen receptor-negative human breast carcinoma cells. J Cell Physiol 155: 556–567, 1993

    Google Scholar 

  22. Sheikh MS, Shao Z-M, Hussain A, Chen J-C, Roberts CT, LeRoith D, Fontana JA: Retinoic acid and estrogen modulation of insulin-like growth factor binding protein-4 gene expression and the estrogen receptor status of human breast carcinoma cells. Biochem Biophys Res Commun 193: 1232–1238, 1993

    Google Scholar 

  23. Haslam SZ: Stromal-epithelial interactions in normal and neoplastic mammary gland. Cancer Treat Res 53: 401–420, 1991

    Google Scholar 

  24. Woodward TL, Xie JW, Haslam SZ: The role of mammary stroma in modulating the proliferative response to ovarian hormones in the normal mammary gland. J MamGland Biol Neoplasia 3: 117–131, 1998

    Google Scholar 

  25. Nap RC, Mol JA, Hazewinkel HAW: Age-related plasma concentrations of growth hormone and insulin-like growth factor in Great Dane pups on different levels of protein intake. Domestic Animal Endocrinol 10: 237–247, 1993

    Google Scholar 

  26. Mol JA, Selman PJ, Sprang EPM, Oosterlaken-Dijksterhuis MA, van Neck JW: IGF and IGF binding protein in plasma and mammary tissue of dogs with progestin induced growth hormone excess. In: Effects of Progestin Administration in the Dog. Thesis, Chapter 9, Utrecht University, Utrecht, 1995

    Google Scholar 

  27. van Zoelen EJJ, van Oostwaard TMJ, van der Saag PT, de Laat SW: Phenotypic transformation of normal rat kidney cells in a growth-factor-defined medium: induction by a neuroblastoma-derived transforming growth factor independently of the EGF receptor. J Cell Physiol 123: 151–160, 1985

    Google Scholar 

  28. Knudsen BS, Harpel PC, Nachman RL: Plasminogen activator inhibitor is associated with the extracellular matrix of cultured bovine smooth muscle cells. J Clin Invest 82: 1082–1089, 1987

    Google Scholar 

  29. Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacterophage T4. Nature 227: 680–685, 1970

    Google Scholar 

  30. Maniatis T, Fritsch EF, Sambrook J: Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA, 1982

    Google Scholar 

  31. Cohick WS, Clemmons DR: The insulin-like growth factors. Annu Rev Physiol 55: 131–153, 1993

    Google Scholar 

  32. Rechler MM, Brown AL: Insulin-like growth factor binding proteins: gene structure and expression. Growth Regulation 2: 55–68, 1992

    Google Scholar 

  33. Grellier P, Yee D, Gonzalez M, Abboud SL: Characterization of insulin-like growth factor binding proteins (IGFBP) and regulation of IGFBP-4 in bone marrow stromal cells. Br J Haematol 90: 249–257, 1995

    Google Scholar 

  34. Kelley KM, Oh Y, Gargosky SE, Gucev Z, Matsumoto T, Hwa V, Ng L, Simpson DM, Rosenfeld RG: Insulin-like growth factor binding proteins (IGFBPS) and their regulatory dynamics. Int J Biochem Cell Biol 28: 619–637, 1996

    Google Scholar 

  35. Clemmons DR: Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev 8: 45–62, 1997

    Google Scholar 

  36. Shemer J, Yaron A, Shao ZM, Sheikh MS, Fontana JA, LeRoith D, Roberts CT: Regulation of insulin-like growth factor (IGF) binding protein-5 in the T47D human breast carcinoma cell line by IGF-I and retinoic acid. J Clin Endocrinol Metab 77: 1246–1250, 1993

    Google Scholar 

  37. Martin JL, Coverley JA, Pattison ST, Baxter RC: Insulinlike growth factor binding protein-3 production by MCF-7 breast cancer cells: stimulation by retinoic acid and cyclic adenosine monophosphate differential effects of estradiol. Endocrinology 136: 1219–1226, 1995

    Google Scholar 

  38. Martin JL, Coverley JA, Baxter RC: Regulation of immunoreactive insulin-like growth factor binding protein-6 in normal and transformed human fibroblasts. J Biol Chem 269: 11470–11477, 1994

    Google Scholar 

  39. Dong Y, Canalis E: Insulin-like growth factor (IGF) I and retinoic acid induce the synthesis of IGF-binding protein 5 in rat osteoblastic cells. Endocrinology 136: 2000–2006, 1995

    Google Scholar 

  40. Zhou Y, Mohan S, Linkhart TA, Baylink DJ, Strong DD: Retinoic acid regulates insulin-like growth factor binding protein expression in human osteoblast cells. Endocrinology 137: 975–983, 1996

    Google Scholar 

  41. Jones JI, Gockerman A, Busby WH, Camacho-Hübner C, Clemmons DR: Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I. J Cell Biol 121: 679–687, 1993

    Google Scholar 

  42. Schmid C, Schlapfer I, Gosteli-Peter MA, Froesch ER, Zapf J: Effects and fate of human IGF-binding protein-5 in rat osteoblast cultures. Am J Physiol 271: E1029–E1035, 1996

    Google Scholar 

  43. Mohan S, Nakao Y, Honda Y, Landale E, Leser U, Dony C, Lang K, Baylink DJ: Studies on the mechanisms by which insulin-like growth factor (IGF) binding protein-4 (IGFBP-4) and IGFBP-5 modulate IGF actions in bone cells. J Biol Chem 270: 20424–20431, 1995

    Google Scholar 

  44. James PL, Stewart CE, Rotwein P: Insulin-like growth factor binding protein-5 modulates muscle differentiation through an insulin-like growth factor-dependent mechanism. J Cell Biol 133: 683–693, 1996

    Google Scholar 

  45. Reeve JG, Guadano A, Xiong J, Morgan J, Bleehen NM: Diminished expression of insulin-like growth factor (IGF) binding protein-5 and activation of IGF-mediated autocrine growth in simian virus 40-transformed human fibroblasts. J Biol Chem 270: 135–142, 1995

    Google Scholar 

  46. Verschure PJ, van Noorden CJF, van Marle J, van den Berg WB: Articular cartilage destruction in experimental inflammatory arthritis: insulin-like growth factor-1 regulation of proteoglycan metabolism in chondrocytes. Histochem J 28: 835–857, 1996

    Google Scholar 

  47. Morales TI: Transforming growth factor-beta and insulinlike growth factor-1 restore proteoglycan metabolism of bovine articular cartilage after depletion by retinoic acid. Arch Biochem Biophys 315: 190–198, 1994

    Google Scholar 

  48. Oh Y: IGF-independent regulation of breast cancer growth by IGF binding proteins. Breast Cancer Res Treat 47: 283–293, 1998.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, The Netherlands

    Marja A. Oosterlaken-dijksterhuis, Marijke M. Kwant, Adri Slob & Jan A. Mol

  2. Department of Pathology, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden

    Eva Hellmén

Authors
  1. Marja A. Oosterlaken-dijksterhuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marijke M. Kwant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adri Slob
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eva Hellmén
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jan A. Mol
    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

Oosterlaken-dijksterhuis, M.A., Kwant, M.M., Slob, A. et al. IGF-I and retinoic acid regulate the distribution pattern of IGFBPs synthesized by the canine mammary tumor cell line CMT-U335. Breast Cancer Res Treat 54, 11–23 (1999). https://doi.org/10.1023/A:1006107703745

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006107703745

Search

Navigation