Skip to main content
SpringerLink
Log in

The insulin-like growth factor binding proteins (IGFBPs) in human breast cancer

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

Summary

Several lines of evidence suggest that IGFs are important regulators of breast cancer cell growth. Unlike other growth factors, the IGFs interact with specific binding proteins in all extracellular fluids. To date, six different IGFBPs have been cloned, although their exact physiological function is not understood. Experimental evidence accumulated over the past few years suggests that IGFBPs could function as modulators of IGF actions in a variety of systems. This includes breast cancer, since several groups have demonstrated the production of IGFBPs by human breast cancer cells. We have found that the pattern of expression of these binding proteins is heterogeneous and varies depending on the breast cancer cell ER status. We have also shown that estrogen is capable of regulating the expression of certain IGFBPs in MCF-7 cells. Specifically, estradiol enhanced the expression of IGFBP 2, 4, and 5, and decreased that of IGFBP-3 in this cell line. Since the IGFBPs can modulate IGF actions in different experimental systems, we and others have studied their potential role as inhibitors of IGF-induced mitogenesis in breast cancer cells. We have demonstrated that purified IGFBP-1 neutralized IGF-dependent growth of MCF-7 cells in a reversible manner. These results suggest that the IGFBPs might be used to inhibit IGF-mediated breast cancer proliferation.

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. Yee D, Cullen KJ, Paik S, Perdue JF, Hampton B, Schwartz A, Lippman ME, Rosen N: Insulin-like growth factor II mRNA expression in human breast cancer. Cancer Res 48:6691–6696, 1988

    Google Scholar 

  2. Osborne CK, Coronado EB, Kitten LJ, Arteaga CL, Fuqua SAW, Ramasharma K, Marshal M, Li CH: Insulin-like growth factor II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via the IGF-I receptor. Mol Endocrinol 3:1701–1709, 1989

    PubMed  Google Scholar 

  3. Cullen KJ, Smith HS, Hill S, Rosen N, Lippman ME: Insulin-like growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions. Cancer Res 51:4978–4985, 1991

    PubMed  Google Scholar 

  4. Yee D, Paik S, Lebovic GS, Marcus RR, Favini RE, Cullen KJ, Lippman ME, Rosen N: Analysis of IGF-I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol Endocrinol 3:509–517, 1989

    PubMed  Google Scholar 

  5. Cullen KJ, Lippman ME, Chow D, Hill S, Rosen N, Zwiebel JA: Insulin-like growth factor-II over-expression in MCF-7 cells induces phenotypic changes associated with malignant progression. Mol Endocrinol 6:91–100, 1992

    PubMed  Google Scholar 

  6. Daly RJ, Harris WH, Wang DY, Darbre PD: Autocrine production of insulin-like growth factor-II using an inducible expression system results in reduced estrogen sensitivity of MCF-7 human breast cancer cells. Cell Growth Differen 2:457–464, 1991

    Google Scholar 

  7. Baxter RC, Martin JL: Binding proteins for the insulin-like growth factors: structure, regulation and function. Prog Growth Factor Res 1:49–68, 1989

    PubMed  Google Scholar 

  8. McCusker RH, Busby WH, Dehoff MH, Camacho-Hubner C, Clemmons DR: Insulin-like growth factor (IGF) binding to cell monolayers is directly modulated by the addition of IGF binding proteins. Endocrinology 129:939–949, 1991

    PubMed  Google Scholar 

  9. Conover CA, Powell DR: Insulin-like growth factor (IGF)-binding protein-3 blocks IGF-induced receptor down-regulation and cell desensitization in cultured bovine fibroblasts. Endocrinology 129:710–716, 1991

    PubMed  Google Scholar 

  10. Lee Y-L, Hintz RL, James PM, Lee PDK, Shively JE, Powell DR: Insulin-like growth factor (IGF) binding protein cDNA from human HEP G2 hepatoma cells: predicted protein sequence suggests an IGF binding domain different from those of the IGF-I and IGF-II receptors. Mol Endocrinol 2:404–411, 1988

    PubMed  Google Scholar 

  11. Binkert C, Landwehr J, Mary J-L, Schwander J, Heinrich G: Cloning, sequence analysis, and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2). EMBO J 8:2497–2502, 1989

    PubMed  Google Scholar 

  12. Shimasaki S, Uchiyama F, Shimonoka M, Ling N: Molecular cloning of the cDNAs encoding a novel insulin-like growth factor binding protein from rat and human. Mol Endocrinol 4:1451–1458, 1990

    PubMed  Google Scholar 

  13. Wood WI, Cachianes G, Henzewl WJ, Winslow GA, Spencer SA, Hellmis R, Martin JL, Baxter RC: Cloning and expression of the growth hormone-dependent insulin-like growth factor-binding protein. Mol Endocrinol 2:1176–1185, 1988

    PubMed  Google Scholar 

  14. Shimasaki S, Shimonaka M, Zhang H-P, Ling N: Identification of five different insulin-like growth factor binding proteins (IGFBPs) from adult rat serum and molecular cloning of a novel IGFBP-5 in rat and human. J Biol Chem 266:10646–10653, 1991

    PubMed  Google Scholar 

  15. Shimasaki S, Gao L, Shimonaka M, Ling N: Isolation and molecular cloning of insulin-like growth factor binding protein-6. Mol Endocrinol 5:938–948, 1991

    PubMed  Google Scholar 

  16. Huff KK, Kaufman D, Gabbay KH, Spencer EM, Lippman ME, Dickson RN: Secretion of an insulin-like growth factor-I-related protein by human breast cancer cells. Cancer Res 46:4613–4619, 1986

    PubMed  Google Scholar 

  17. Minuto F, Del Monte P, Barreca A, Nicolin A, Giordano G: Partial characterization of somatomedin C-like immunoreactivity secreted by breast cancer cells in vitro. Mol Cell Endocrinol 54:179–184, 1987

    PubMed  Google Scholar 

  18. De Leon DD, Bakker B, Wilson DM, Hintz RL, Rosenfeld RG: Demonstration of insulin-like growth factor (IGF-I and II) receptors and binding protein in human breast cancer cell lines. Biochem Biophys Res Commun 152:398–405, 1988

    PubMed  Google Scholar 

  19. De Leon DD, Wilson DM, Bakker B, Lamson G, Hintz RL, Rosenfeld RG: Characterization of insulin-like growth factor binding proteins from human breast cancer. Mol Endocrinol 3:567–574, 1989

    PubMed  Google Scholar 

  20. Yee D, Favoni RE, Lupu R, Cullen KJ, Lebovic GS, Huff KK, Lee PDK, Lee YL, Powell DR, Dickson RB, Rosen N, Lippman ME: The insulin-like growth factor binding protein BP-25 is expressed by human breast cancer cells. Biochem Biophys Res Commun 158:38–44, 1989

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  22. Yee D, Favoni RE, Lippman ME, Powell DR: Identification of insulin-like growth factor binding proteins in breast cancer cells. Breast Cancer Res Treat 18:3–10, 1991

    PubMed  Google Scholar 

  23. Yee D, Shimasaki S, Powell DR, McGuire WL Jr, Jackson JG: The patterns of insulin-like growth factor binding protein (IGFBP) expression in breast cancer cells suggest a strategy for their use as IGF inhibitors. Breast Cancer Res Treat 19:211, 1991

    Google Scholar 

  24. Dickson RB, Lippman ME: Estrogenic regulation of growth and polypeptide growth factor secretion in human breast carcinoma. Endocr Rev 8:29–43, 1987

    PubMed  Google Scholar 

  25. Stewart AJ, Johnson MD, May FEB, Westley BR: Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J Biol Chem 2165:21172–21178, 1990

    Google Scholar 

  26. Katzenellenbogen BS, Norman MJ: Multihormonal regulation of the progesterone receptor in MCF-7 human breast cancer cells: interrelationships among insulin/insulin-like growth factor I, serum, and estrogen. Endocrinology 126:891–898, 1990

    PubMed  Google Scholar 

  27. LaTour D, Mohan S, Linkhart TA, Baylink DJ, Strong DD: Inhibitory insulin-like growth factor binding protein: cloning, complete sequence, and physiological regulation. Mol Endocrinol 4:1806–1814, 1990

    PubMed  Google Scholar 

  28. Ahmed SR, Manni A, Gray G, Hammond JM: Characterization and hormonal regulation of radioimmunoassayable IGF-I (insulin-like growth factor I) like activity and IGF-binding proteins secreted by human breast cancer cells. Anticancer Res 10:1217–1224, 1990

    PubMed  Google Scholar 

  29. Kim I, Manni A, Lynch J, Hammond JM: Identification and regulation of insulin-like growth factor binding proteins produced by hormone-dependent and hormone-independent human breast cancer cell lines. Mol Cell Endocrinol 78:71–78, 1991

    PubMed  Google Scholar 

  30. Camacho-Hubner C, McCusker RH, Clemmons DR: Secretion and biological actions of insulin-like growth factor binding proteins in two human tumor-derived cell lines. J Cell Physiol 148:281–289, 1991

    PubMed  Google Scholar 

  31. Glikman PL, Manni A, Bartholomew M, Demers L: Polyamine involvement in basal and estradiol-stimulated insulin-like growth factor I secretion and action in breast cancer cells in culture. J Steroid Biochem 37:1–10, 1990

    PubMed  Google Scholar 

  32. Fraker LD, Halter SA, Forbes JT: Growth inhibition by retinol of a human breast carcinoma cell line in vitro and in athymic mice. Cancer Res 44:5757–5763, 1984

    PubMed  Google Scholar 

  33. Marth C, Bock G, Daxenbichler G: Effects of 4-hydroxyphenylretinamide and retinoic acid on proliferation and cell cycle of human breast cancer cells. J Natl Cancer Inst 75:871–875, 1985

    PubMed  Google Scholar 

  34. Sporn MB, Roberts AB, Roche NS, Agechina H, Shudo K: Mechanisms of action of retinoids. J Am Acad Dermatol 15:756–764, 1986

    PubMed  Google Scholar 

  35. Fontana JA, Burrows-Mezu A, Clemmons DR, LeRoith D: Retinoid modulation of insulin-like growth factor binding proteins and inhibition of breast carcinoma proliferation. Endocrinology 128:1115–1122, 1991

    PubMed  Google Scholar 

  36. Baxter RC: Insulin-like growth factor (IGF) binding proteins: the role of IGFBPs in regulating IGF availability. Acta Paediatr Scand (suppl) 372:107–114, 1991

    Google Scholar 

  37. Blum WF, Jenne EW, Reppin F, Kietzmann K, Ranke MB, Bierich JR: Insulin-like growth factor I (IGF-I)-binding protein complex is a better mitogen than free IGF-I. Endocrinology 125:766–772, 1989

    PubMed  Google Scholar 

  38. De Mellow JS, Baxter RC: Growth hormone-dependent insulin-like growth factor (IGF) binding protein both inhibits and potentiates IGF-stimulated DNA synthesis in human skin fibroblasts. Biochem Biophys Res Commun 156:199–204, 1988

    PubMed  Google Scholar 

  39. Elgin RG, Busby WH, Clemmons DR: An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I. Proc Natl Acad Sci USA 84:3254–3258, 1987

    PubMed  Google Scholar 

  40. Clemmons DR, Gardner LI: A factor contained in plasma is required for IGF binding protein-1 to potentiate the effect of IGF-I on smooth muscle cell DNA synthesis. J Cell Physiol 145:129–135, 1990

    PubMed  Google Scholar 

  41. Brewer MT, Stetler GL, Squires CH, Thompson RC, Busby WH, Clemmons DR: Cloning, characterization, and expression of a human insulin-like growth factor binding protein. Biochem Biophys Res Commun 152:1289–1297, 1988

    PubMed  Google Scholar 

  42. Jones JI, D'Ercole J, Camacho-Hubner C, Clemmons DR: Phosphorylation of insulin-like growth factor (IGF)-binding protein-1 in cell culture and in vivo: effects on affinity for IGF-1. Proc Natl Acad Sci USA 88:7481–7485, 1991

    PubMed  Google Scholar 

  43. Knauer DJ, Smith GL: Inhibition of biological activity of multiplication-stimulating activity by binding to its carrier protein. Proc Natl Acad Sci USA 77: 7252–7256, 1980

    PubMed  Google Scholar 

  44. Herrington AC, Kuffer AD: Identification of a specific inhibitor of nonsuppressible insulin-like activity in a partially purified human serum fraction. Endocrinology 109:1634–1640, 1981

    PubMed  Google Scholar 

  45. Koistinen R, Itkonen O, Selenius P, Seppala N: Insulin-like growth factor binding protein-1 inhibits binding of IGF-I on fetal fibroblasts but stimulates their DNA synthesis. Biochem Biophys Res Commun 173:408–415, 1990

    PubMed  Google Scholar 

  46. Liu L, Brinkman A, Blat C, Harel L: IGFBP-1, an insulin-like growth factor binding protein, is a cell growth inhibitor. Biochem Biophys Res Commun 174:673–679, 1991

    PubMed  Google Scholar 

  47. Ritvos O, Ranta T, Jalkanen J, Suikkari AM, Voutilainen R, Bohn H, Rutanen EM: Insulin-like (IGF) growth factor binding protein from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells. Endocrinology 122:2150–2157, 2988

  48. Campbell P, Novak JF: Insulin-like growth factor binding protein (IGFBP) inhibits IGF action on human osteosarcoma cells. J Cell Physiol 149:293–300, 1991

    PubMed  Google Scholar 

  49. Colouscou JM, Shoyab M: Purification of a colon cancer cell growth inhibitor and its identification as an insulin-like growth factor binding protein. Cancer Res 51:2813–2819, 1991

    PubMed  Google Scholar 

  50. van der Burg B, Isbrucker L, van Selm-Miltenburg AJP, de Laat SW, van Zoelen EJJ: Role of estrogen-induced insulin-like growth factors in the proliferation of human breast cancer cells. Cancer Res 50:7770–7774, 1990

    PubMed  Google Scholar 

  51. McGuire WL Jr, Jackson JG, Figueroa JA, Shimasaki S, Powell DR, Yee D: Regulation of breast cancer cell growth by the insulin-like growth factor binding proteins: use of IGFBP-1 as an inhibitor of IGF action. J Natl Cancer Inst (submitted), 1992.

  52. Aaronson SA: Growth factors and cancer. Science 254:1146–1153, 1991

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Oncology, University of Texas Health Science Center, 78284-7884, San Antonio, Texas, USA

    José A. Figueroa & Douglas Yee M.D.

Authors
  1. José A. Figueroa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Douglas Yee M.D.
    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

Figueroa, J.A., Yee, D. The insulin-like growth factor binding proteins (IGFBPs) in human breast cancer. Breast Cancer Res Tr 22, 81–90 (1992). https://doi.org/10.1007/BF01833336

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01833336

Key words

Search

Navigation