Skip to main content
Log in

Function of the IGF-I Receptor in Breast Cancer

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The insulin-like growth factor-I receptor (IGF-IR)3 is a transmembrane tyrosine kinaseregulating various biological processes such as proliferation, survival, transformation, differentiation,cell-cell and cell-substrate interactions. Different signaling pathways may underlie thesepleiotropic effects. The specific pathways engaged depend on the number of activated IGF-IRs,availability of intracellular signal transducers, the action of negative regulators, and is influencedby extracellular modulators. Experimental and clinical data implicate the IGF-IR in breastcancer etiology. There is strong evidence linking hyperactivation of the IGF-IR with theearly stages of breast cancer. In primary breast tumors, the IGF-IR is overexpressed andhyperphosphorylated, which correlates with radio-resistance and tumor recurrence. In vitro,the IGF-IR is often required for mitogenesis and transformation, and its overexpression oractivation counteract effects of various pro-apoptotic treatments. In hormone-responsive breastcancer cells, IGF-IR function is strongly linked with estrogen receptor (ER) action. TheIGF-IR and the ER are co-expressed in breast tumors. Moreover, estrogens stimulate the expressionof the IGF-IR and its major signaling substrate IRS-1, while antiestrogens downregulateIGF-IR signaling, mainly by decreasing IRS-1 expression and function. On the other hand,overexpression of IRS-1 promotes estrogen-independence for growth and transformation. InER-negative breast cancer cells, usually displaying a more aggressive phenotype, the levelsof the IGF-IR and IRS-1 are often low and IGF is not mitogenic, yet the IGF-IR is stillrequired for metastatic spread. Consequently, IGF-IR function in the late stages of breastcancer remains one of the most important questions to be addressed before rationalanti-IGF-IR therapies are developed.

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

Access this article

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. H. Werner, M. Woloschak, B. Stannard, Z. Shen-Orr, C. T. Roberts, Jr., and D. LeRoith (1991). The insulin-like growth factor receptor: Molecular biology, heterogeneity, and regulation. In D. LeRoith (ed.), Insulin-like Growth Factors: Molecular and Cellular Aspects, Boca-Raton, CRC Press, pp. 18–48.

    Google Scholar 

  2. A. Morrione, B. Valentinis, S. Q. Xu, G. Yumet, A. Louvi, A. Efstradiadis, and R. Baserga (1997). Insulin-like growth factor II stimulates cell proliferation through the insulin receptor. Proc. Natl. Acad. Sci. U.S.A. 15:3777–3782.

    Google Scholar 

  3. R. Baserga (1998). The IGF-IR receptor in normal and abnormal growth. In R. Dickson, and D. S. Salomon (eds.), Hormones and Growth Factors in Development and Neoplasia, Wiley-Liss, Inc., pp. 269–287.

  4. E. Surmacz, M. Guvakova, M. Nolan, R. Nicosia, and L. Sci acca (1998). Type I insulin-like growth factor receptor function in breast cancer. Breast Cancer Res. Treat. 47:255–267.

    Google Scholar 

  5. R. O'Connor (1998). Survival factors and apoptosis. In T. Scheper (ed.), Adv. Biochem. Engin/Biotech. Springer-Ver lag, 62:138–166.

  6. A. A. Butler, S. Yakar, I. H. Gewolb, M. Karas, Y. Okubo, and D. LeRoith (1998). Insulin-like growth factor-I receptor signal transduction: At the interface between physiology and cell biology. Comp. Biochem. Physiol. Part B 121:19–26.

    Google Scholar 

  7. A. Ullrich, A. Gray, A. W. Tam, T. Yang-Feng, M. Tsubokawa, C. Collins, W. Henzel, T. Le Bon, S. Kathuria, E. Chen, S. Jacobs, U. Francke, J. Ramachndran, and Y. Fujita-Yama guchi (1986). Insulin-like growth factor I receptor primary structure: Comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J. 5:2503–2512.

    Google Scholar 

  8. H. Werner (1998). Dysregulation of the type 1 IGF receptor as a paradigm in tumor progression. Mol. Cell. Endocrinol. 141:1–5.

    Google Scholar 

  9. L. Sepp-Lorenzino (1998). Structure and function of the insulin-like growth factor I receptor. Breast Cancer Res. Treat. 47:235–253.

    Google Scholar 

  10. A. Hongo, C. D'Ambrosio, M. Miura, A. Morrione, and R. Baserga (1996). Mutational analysis of the mitogenic and transforming activities of the insulin-like growth factor I recepand tor. Oncogene 12:1231–1238.

    Google Scholar 

  11. V. A. Blakesley, A. P. Koval, B. S. Stannard, A. Scrimgeour, and D. LeRoith (1998). Replacement of tyrosine 1251 in the carboxyl terminus of the insulin-like growth factor-I receptor disrupts the actin cytoskeleton and inhibits proliferation and anchorage-independent growth. J. Biol. Chem. 273:18411–18422.

    Google Scholar 

  12. M. F. White (1998). The IRS-signalling system: A network of docking proteins that mediate insulin action. Mol. Cell. Biochem. 182:3–11.

    Google Scholar 

  13. P. R. Shepherd, D. Withers, and K. Siddle (1998). Phosphoino-sitide 3-kinase: The key switch mechanism in insulin signaling. Biochem. J. 333:471–490.

    Google Scholar 

  14. S. Hashemolhosseinin, Y. Nagamine, S. J. Morley, S. Desrivieres, L. Marcep, and S. Ferrari (1998). Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J. Biol. Chem. 273:14424–14429.

    Google Scholar 

  15. M. L. Goalstone and B. Draznin (1998). What does insulin do to Ras? Cell Sign. 10:279–301.

    Google Scholar 

  16. M. Rubini, A. Hongo, C. D'Ambrosio, and R. Baserga (1997). The IGF-IR in mitogenesis and transformation of mouse embryo fibroblasts: Role of receptor number. Exp. Cell Res. 230:284–292.

    Google Scholar 

  17. K. Reiss, B. Valentinis, X. Tu, S-Q. Xu, and R. Baserga (1998). Molecular markers of IGF-I-mediated mitogenesis. Exp. Cell Res. 242:361–372.

    Google Scholar 

  18. M. Resnicoff, J-L. Burgaud, H. Rotman, D. Abraham, and R. Baserga (1995). Correlation between apoptosis, tumorigenesis, and levels of insulin-like growth factor I receptors. Cancer Res. 55:3739–3741.

    Google Scholar 

  19. A. A. Butler, V. A. Blakesley, M. Tsokos, V. Pouliki, T. Wood, and D. LeRoith (1998). Stimulation of tumor growth by recom binant human insulin-like growth factor-I (IGF-I) is dependent substrateon the dose and the level of IGF-I receptor expression. Cancer Res. 58:3021–3027.

    Google Scholar 

  20. E. Surmacz, C. Sell, J. Swantek, H. Kato, C. T. Roberts, Jr., D. Le Roith, and R. Baserga (1995). Dissociation of mitogenesis and transforming activity by C-terminal truncation of the insulin-like growth factor-I receptor. Exp. Cell Res. 218:370–380.

    Google Scholar 

  21. B. Valentinis, A. Morrione, S. J. Taylor, and R. Baserga (1997). insulin-like growth factor I receptor signaling in transformation by src oncogenes. Mol. Cell. Biol. 7:3744–3754.

    Google Scholar 

  22. M. Nolan, L. Jankowska, M. Prisco, S. Xu, M. Guvakova, and E. Surmacz (1997). Differential roles of ARS-1 and SHC signaling pathways in breast cancer calls. Int. J. Cancer 72: 828–834.

    Google Scholar 

  23. M. A. Guvakova and E. Surmacz (1999). Overexpressed IGF-IR induce reorganization of actin cytoskeleton and dephosphorylation of focal adhesion proteins: GAK, Cas, and paxilln. Exx. Cell Res. 251:244–255.

    Google Scholar 

  24. T. Petley, K. Graff, W. Jaang, H. Yang, and J. Florini (1999). Variation among cell types in the signaling pathways by which IGF-I stimulates specific cellular responses. Horm. Metabol. Res. 31:70–76.

    Google Scholar 

  25. E. Surmacz and J-L. Burgaud (1995). Overexpression of IRS-1 in the human breast cancer cell line MCF-7 induces loss of estrogen requirements for growth and transformation. Clin. Cancer Res. 1:1429–1436.

    Google Scholar 

  26. C. D'Ambrosio, S. Keller, A. Morrione, G. E. Lienhard, R. Baserga, and E. Surmacz (1995). Transforming potential of the insulin receptor substrate 1 (IRS-1). Cell Growth Differ. 6:557–562.

    Google Scholar 

  27. L. Mauro, D. Sisci, M. Bartucci, M. Salerno, J. Kim, T. Tam, M. Guvakova, S. Ando', and E. Surmacz (1999). SHC-alpha5 beta1 integrin interactions regulate breast cancer cell adhesion and motility. Exp. Cell Res. 252:439–448.

    Google Scholar 

  28. B. Valentinis, A. Morrione, F. Peruzzi, M. Prisco, K. Reiss, and R. Baserga (1999). Anti-apoptotic signaling of the IGF-I receptor in fibroblasts following loss of matrix adhesion. Oncogene 18:1827–1836.

    Google Scholar 

  29. M. A. Guvakova and E. Surmacz (1997). Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival and promote cell-cell adhesion in human breast cancer cells. Exp. Cell Res. 231:149–162.

    Google Scholar 

  30. J. G. Jackson, M. F. White, and D. Yee (1998). Insulin receptor substrate-1 is the predominant signaling molecule activated by insulin-like growth factor I, insulin, and interleukin-4 in estrogen receptor-positive human breast cancer cells. J. Biol. Chem. 273:9994–10003.

    Google Scholar 

  31. S. E. Dunn, R. A. Hardman, F.W, Kari, and J. C. Barrett (1997). Insulin-like growth factor 1 (IGF-1) alters drug sensitivity of HBL100 human breast cancer cells by inhibition of apoptosis induced by diverse anticancer drugs. Cancer Res. 57: 2687–2693.

    Google Scholar 

  32. M. A. Guvakova and E. Surmacz (1997). Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells. Cancer Res. 57:2606–2610.

    Google Scholar 

  33. M. R. Daws, B. R. Westley, and F. E. B. May (1996). Paradoxi cal effects of overexpression of the type I insulin-like growth factor (IGF) receptor on the responsiveness of human breast cancer cells to IGFs and estradiol. Endocrinology 137: 1177–1186.

    Google Scholar 

  34. A. J. Stewart, M. D. Johnson, F. E. B. May, and B. R. Westley (1990). Role of insulin-like growth factors and the type I insu lin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J. Biol. Chem. 265: 21172–21178.

    Google Scholar 

  35. A. V. Lee, J. G. Jackson, J. L. Gooch, S. G. Hilsenbeck, E. Coronado-Heinsohn, C. K Osborne, and D. Yee (1999). Enhancement of insulin-like growth factor signaling in human breast cancer: Estrogen regulation of insulin receptor substrateon 1 expression in vitro and in vivo. Mol. Endocrinol. 10: 787–796.

    Google Scholar 

  36. M. Salerno, D. Sisci, L. Mauro, M. Guvakova, S. Ando', and E. Surmacz (1999). Insulin-receptor substrate 1 (IRS-1) is a substrate for a pure antiestrogen ICI 182,780. Int. J. Cancer 81:299–304.

    Google Scholar 

  37. A. de Cupis and R. E. Favoni (1997). Oestrogen/growth factor cross-talk in breast carcinoma: a specific target for novel antiesby trogens. Trends Pharmcol. Sci. 18:245–251.

    Google Scholar 

  38. A. de Cupis, D. Noonan, P. Pirani, A. Ferrera, L. Clerico, and R. E. Favoni (1995). Comparison between novel steroid-like and conventional nonsteroidal antioestrogens in inhibiting oes tradiol-and IGF-I-induced proliferation of human breast can cer-derived cells. Br. J. Pharm. 116:2391–2400.

    Google Scholar 

  39. G. Freiss, C. Puech, and F. Vignon (1998). Extinction of insulinof like growth factor-I mitogenic signaling by antiestrogen-stimu lated FAS-associated protein tyrosine phosphatase-1 in human breast cancer cells. Mol. Endocrinol. 12:568–579.

    Google Scholar 

  40. J. L. Resnic, D. B. Reichart, K. Huey, N. J. G. Webster, and B. L. Seely (1998). Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. Cancer Res. 58:1159–1164.

    Google Scholar 

  41. B. C. Turner, B. G. Haffty, L. Narayanann, J. Yuan, P. A. Havre, A. Gumbs, L. Kaplan, J-L. Burgaud, D. Carter, R. Baserga, and P. M. Glazer (1997). IGF-I receptor and cyclin D1 expression influence cellular radiosensitivity and local breast Correlacancer recurrence after lumpectomy and radiation. Cancer Res. 57:3079–3083.

    Google Scholar 

  42. V. Pezzino, V. Papa, G. Milazzo, B. Gliozzo, P. Russo, and P. L. Scalia (1996). Insulin-like growth factor-I (IGF-I) receptors in breast cancer. Ann N.Y. Acad Sci. 784:189–201.

    Google Scholar 

  43. J. P. Peyrat and J. Bonneterre (1992). Type 1 IGF receptor in human breast diseases. Breast Cancer Res. Treat. 22:59–67.

    Google Scholar 

  44. E. M. Berns, J. G. M. Klijn, I. L. van Staveren, H. Portengen, and J. A. Foekens (1992). Sporadic amplification of the insulincell like growth factor I receptor gene in human breast cancer. Cancer Res. 52:1036–1039.

    Google Scholar 

  45. M. Prisco, A. Hongo, M. G. Rizzo, A. Sacchi, and R. Baserga (1997). The insulin-like growth factor I receptor as a physiolog ically relevant target of p53 in apoptosis caused by interleukin-3 withdrawal. Mol. Cell. Biol. 17:1084–1092.

    Google Scholar 

  46. H. Werner, E. Karnieli, F. J. Rauscher III, and D. LeRoith (1996). Wild type and mutant p53 differentially regulate transcription of insulin-like growth factor I receptor gene. Proc. Natl. Acad. Sci. U.S.A. 93:8318–8323.

    Google Scholar 

  47. R. L. Rocha, S. G. Hilsenbeck, J. G. Jackson, C. L. Van Der Berg, C-W. Weng, A. V. Lee, and D. Yee (1997). Insulin-like growth factor-binding protein 3 and insulin receptor substrate 1 in breast cancer: Correlation with clinical parameters and disease-free survival. Clin. Cancer Res. 3:103–109.

    Google Scholar 

  48. M. A. Soos, B. T. Nave, and K. Siddle (1993). Immunological studies of type I IGF receptors and insulin receptors: Characterization of hybrid and atypical receptor subtypes. Adv. Exp. Med. Biotech. 343:145–157.

    Google Scholar 

  49. M. J. Railo, K. Smitten, and F. Pekonen (1994). The prognostic value of insulin-like growth factor I in breast cancer. Results insulinof a follow-up study on 126 patients. Eur. J. Cancer 30A: 307–311.

    Google Scholar 

  50. F. Pekonnen, S. Partangen, T. Makinen, and E-M. Rutanen (1988). Receptors for epidermal growth factor and insulin-like growth factor I and their relation to steroid receptors in human breast cancer. Cancer Res. 48:1343–1374.

    Google Scholar 

  51. J. A. Foekens, H. Portengen, M. Janssen, and J. G. M. Klijn (1989). Insulin-like growth factor I receptors and insulin-like activity in human primary breast cancer. Cancer 63:2139–2147.

    Google Scholar 

  52. L. E. Stevenson and A. R. Frackelton, Jr. (1998). Constitutively tyrosine phosphorylated p52 Shc in breast cancer cells: Correlacancer tion with ERB2 and p66 She expression. Breast Cancer Res. Treat. 49:119–128.

    Google Scholar 

  53. J. S. Biscardi, A. P. Belsches, and S. J. Pearsons (1998). Charac terization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. Mol. Carcino gen. 21:261–272.

    Google Scholar 

  54. J. P. Peyrat, J. Bonneterre, I. Dusanter-Fourt, B. Leroy-Martin, J. Dijane, and A. Demaille. (1989). Characterization of insulin-like growth factor 1 receptors (IGF-IR) in human breast cancer insulincell lines. Bulletin Cancer 76:311–319.

    Google Scholar 

  55. L. Sepp-Lorenzino, N. Rosen, and D. Lebwohl (1994). Insulin and insulin-like growth factor signaling are defective in MDA-MB-468 human breast cancer cell line. Cell Growth Differ. 5:1077–1083.

    Google Scholar 

  56. M. Doerr and J. Jones (1996). The roles of integrins and extra-cellular matrix proteins in the IGF-IR-stimulated chemotaxis of human breast cancer cells. J. Biol. Chem. 271:2443–2447.

    Google Scholar 

  57. C. L. Arteaga, L. J. Kitten, E. B. Coronado, S. Jacobs, F. C. Kull, Jr., D. C. Allred, and C. K. Osborne (1989). Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J. Clin. Invest. 84: 1418–1423.

    Google Scholar 

  58. S. E. Dunn, M. Ehrlich, N. J. H. Sharp, K. Reiss, G. Solomon, R. Hawkins, R. Baserga, and J. C. Barrett (1998). A'dominant negative mutant of the insulin-like growth factor I receptor inhibits the adhesion, invasion and metastasis of breast cancer. Cancer Res. 58:3353–3361.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Surmacz, E. Function of the IGF-I Receptor in Breast Cancer. J Mammary Gland Biol Neoplasia 5, 95–105 (2000). https://doi.org/10.1023/A:1009523501499

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009523501499

Navigation