Abstract
IGF1 and IGF2 are circulating peptide hormones and locally-acting growth factors with both paracrine and autocrine functions. IGF1 and IGF2 signal through a common tyrosine kinase receptor, the insulin- like growth factor 1 receptor (IGF1R), and have mitogenic, cell survival, and insulin-like actions that are essential for embryogenesis, post-natal growth physiology, and breast development. The activities of IGF1 and 2 are tightly-regulated by a network of binding proteins and targeted degradation mechanisms. This complex regulatory system is disrupted in breast cancer, leading to excess IGF1R signaling. Evidence for this statement includes: a) breast cancers are infiltrated with IGF2 expressing stromal cells; b) mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) is mutated in breast cancer, leading to loss of IGF2 degradation; c) IGF1R is overexpressed by malignant breast epithelial cells, and in some cases IGF1R is amplified; and d) complex changes in IGF binding protein expression occur during breast cancer progression which most likely also affect IGF1 and 2 signaling. The clinical importance of these epigenetic and genetic changes has recently been stressed by the finding that IGF1R signaling alters the apoptotic response of breast cancer cells to genotoxic stress and, in addition, IGF1R activation sensitizes cells to estrogen by inducing phosphorylation of the estrogen receptor. As a consequence of these findings, we propose that IGF analysis of breast cancer samples should shift from prognostic studies to an evaluation of IGF ligands, receptors, and binding proteins as resistance/sensitivity markers for radiation, chemotherapy, and endocrine therapy.
Similar content being viewed by others
References
Ellis M, Garmroudi F, Cullen K: Insulin receptors (IGF1 and IGF2). In: Bertino J (ed) Encyclopedia of Cancer, Vol 2. Academic Press, San Diego, 1997, pp 927-939
Siddle K, Soos M, Field C, et al: Hybrid and atypical insulin/insulin-like growth factor I receptors. Horm Res 41(Suppl 2):56-64, 1994
Morrione A, Valentinis B, Xu S-Q, et al: Insulin-like growth factor II stimulates cell proliferation through the insulin receptor. Proc Natl Acad Sci USA 94:3777-3782, 1997
Clemmons RD: Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine and Growth Factor Rev 8:45-62, 1997
Oh Y: IGF-independent regulation of breast cancer growth by IGF binding proteins. Breast Cancer Res Treat 47:283-293, 1998
Ellis MJC, Leav BA, Yang Z, et al: Affinity for the insulin-like growth factor-II (IGF-II) receptor inhibits autocrine IGF-II activity in MCF-7 breast cancer cells. Mol Endocrinol 10:286-297, 1996
Formisano P, Najjar S, Gross C, et al: Receptor-mediated internalization of insulin. Potential role of pp120/HA4, a substrate of the insulin receptor kinase. J Biol Chem 270:24073-24077, 1995
Yee D: The insulin-like growth factors and breast cancer — revisited. Breast Cancer Res Treat 47:197-199, 1998
Stewart A, Johnson M, May F, et al: Role of insulin-like growth factors and type I insulin-like growth factor receptor in the estrogen stimulated proliferation of human breast cancer cells. J Biol Chem 265:31172-21178, 1990
Kleinberg D: Role of IGF-I in normal mammary development. Breast Cancer Res Treat 47:201-208, 1998
Ruan W, Newman C, Kleinberg D: Intact and aminoterminally shortened forms of insulin-like growth factor I induce mammary gland differentiation and development. Proc Natl Acad Sci USA 89:10872-10876, 1992
Ruan W, Catanese V, Wieczorek R, et al: Estradiol enhances the stimulatory effect of insulin-like growth factor-1 (IGF1) on mammary development and growth hormone-induced IGF1 messenger ribonucleic acid. Endocrinol 136:1296-1302, 1995
el-Tanani M, Green C: Insulin/IGF-1 modulation of the expression of two estrogen-induced genes in MCF-7 cells. Mol Cell Endocrinol 121:29-35, 1996
Lee A, Weng C, Jackson J, et al: Activation of estrogen receptor-mediated gene transcription by IGF1 in human breast cancer cells. J Endocrinol 152:39-47, 1997
Hafner F, Holler E, von Angerer E: Effect of growth factors of estrogen mediated gene expression. J Steroid Biochem Molec Biol 58:385-393, 1996
Kato S, Endoh H, Masuhiro Y. et al: Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270:1491-1494, 1995
Sweeney KJ, Musgrove EA, Watts CK, et al: Cyclins and breast cancer [review]. Cancer Treat Res 83:141-70, 1996
Zwijsen R, Wientjens E, Klompmaker R, et al: CDK-independent activation of estrogen receptor by cyclin D1. Cell 88:405-415, 1997
Furlanetto R, Harwell S, Frick K: Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro. Mol Endocrinol 8:510-517, 1994
Guvakova M, Surmacz E: Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell-cell adhesion in human breast cancer cells. Exp Cell Res 231:149-162, 1997
de Cupis A, Noonan D, Pirani P, et al: Comparison between novel steroid-like and conventional nonsteroidal antioestrogens in inhibiting oestradiol-and IGF-I-induced proliferation of human breast cancer-derived cells. Br J Pharmacol 116:2391-2400, 1995
Harrington EA, Bennett MR, Fanidi A, et al: c-myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J 13:3286-3295, 1994
Christofori G, Naik P, Hanahan D: A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 369:414-418, 1994
Baserga R: The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res 55:249-252, 1995
Bates P, Fisher R, Ward A, et al: Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF-II). Br J Cancer 72:1189-1193, 1995
Buckbinder L, Talbott R, Velasco-Miguel S, et al: Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377:646-649, 1995
Zhang L, Kashanchi F, Zhan Q, et al: Regulation of insulin-like growth factor II P3 promotor by p53: a potential mechanism for tumorigenesis. Cancer Res 56:1367-1373, 1996
Webster N, Resnik J, Reichart D, et al: Repression of the insulin receptor promoter by the tumor suppressor gene product p53: a possible mechanism for receptor overexpression in breast cancer. Cancer Res 56:2781-2788, 1996
Sell C, Baserga R, Rubin R: Insulin-like growth factor I (IGF-I) and the IGF-1 receptor prevent etoposide-induced apoptosis. Cancer Res 55:303-306, 1995
Turner B, Haffty B, Narayanan L, et al: Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res 57:3079-3083, 1997
Rasmussen A, Cullen K: Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors. Breast Cancer Res Treat 47:219-233, 1998
Giani C, Cullen KJ, Campani D, et al: IGF-II mRNA and protein are expressed in the stroma of invasive breast cancers: an in situ hybridization and immunohistochemical study. Breast Cancer Res Treat 41:43-50, 1996
Cullen KJ, Smith HS, Hill S, et al: Growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions. Cancer Res 51:4978-4985, 1991
Singer C, Rasmussen A, Smith H, et al: Malignant breast epithelium selects for IGF-II expression in breast stroma. Evidence for paracrine function. Cancer Res 55:2448-2454, 1995
Ellis MJC, Singer C, Hornby A, et al: Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res Treat 31:249-261, 1994
Huynh H, Alpert L, Pollak M: Pregnancy-dependent growth of mammary tumors is associated with overexpression of insulin-like growth factor II. Cancer Res 56:3651-3654, 1996
Manni A, Badger B, Wei L, et al: Hormonal regulation of insulin-like growth factor-II and insulin-like growth factor-binding protein expression by breast cancer cells in vivo. Evidence for stromal epithelial interactions. Cancer Res 54:2934-2942, 1994
Torapainen E, Lipponen P, Syrjanen K: Expression of insulin-like growth factor II in female breast cancer as related to established prognostic factors and long term prognosis. Anticancer Res 15:2669-2674, 1995
Yu H, Levesque M, Khosravi M, et al: Associations between insulin-like growth factors and their binding proteins and other prognostic indicators in breast cancer. Br J Cancer 74:1242-1247, 1996
Foekens JA, Portengen H, van Putten WLJ, et al: Prognostic value of receptors for insulin-like growth factor 1, somatostatin, and epidermal growth factor in human breast cancer. Cancer Res 49:7002-7009, 1989
Papa V, Gliozzo B, Clark GM, et al: Insulin-like growth factor receptors are overexpressed and predict a low risk in human breast cancer. Cancer Research 53:3736-3740, 1993
Peyrat J, Bonneterre J, Vennin P, et al: Insulin-like growth factor 1 receptors (IGF1-R) and IGF1 in human breast tumors. J Steroid Biochem Mol Biol 37:823-827, 1990
Bonneterre J, Peyrat J, Beuscart R, et al: Prognostic significance of insulin-like growth factor 1 receptors in human breast cancer. Cancer Res 50:6931-6935, 1990
Surmacz E, Guvakova M, Nolan M, et al: Type I insulin-like growth factor receptor function in breast cancer. Breast Cancer Res Treat 47:255-267, 1998
Clarke R, Howell A, Anderson E: Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen and progesterone. Br J Cancer 75:251-257, 1997
Almeida A, Muleris M, Dutrillaux B, et al: The insulin-like growth factor I receptor gene is the target for the 15q26 amplicon in breast cancer. Genes Chromosomes Cancer 11:63-65, 1994
Happerfield L, Miles D, Barnes D, et al: The localization of the insulin-like growth factor receptor 1 (IGFR1) in benign and malignant breast tissue. Proc AACR Abstract #374, 1997
Soos M, Field C, Lammers R, et al: A panel of monoclonal antibodies for the type I insulin-like growth factor receptor. J Biol Chem 267:12955-12963, 1992
Railo M, von Smitten K, Pekonen F: The prognostic value of insulin-like growth factor-I receptor in breast cancer patients. Results of a follow-up study on 126 patients. Eur J Cancer 30A:307-311, 1994
Hankins GR, De Souza AT, Bentley RC, et al: M6P/IGF2 receptor: a candidate breast tumor suppressor gene. Oncogene 12:2003-2009, 1996
Oates A, Schumaker L, Jenkins S, et al: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), a putative breast tumor suppressor gene. Breast Cancer Res Treat 47:269-281, 1998
Claussen M, Buergisser D, Schuller AGP, et al: Regulation of insulin-like growth factor (IGF)-binding protein-6 and mannose 6-phosphate/IGF-II receptor expression in IGF-II-overexpressing NIH 3T3 cells. Mol Endocrinol 9:902-912, 1995
Rocha R, Hilsenbeck S, Jackson J, et al: 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, 1997
Rocha RL, Hilsenbeck SG, Jackson JG, et al: Correlation of insulin-like growth factor-binding protein-3 messenger RNA with protein expression in primary breast cancer tissues: detection of higher levels in tumors with poor prognostic features. J Natl Cancer Inst 88:601-606, 1996
Pratt S, Pollak M: Estrogen and antiestrogen modulation of MCF7 human breast cancer cell proliferation is associated with specific alterations in accumulation of insulin-like growth factor-binding proteins in conditioned media. Cancer Res 53:5193-5198, 1993
Pratt S, Pollak M: Insulin-like growth factor binding protein 3 (IGF-BP3) inhibits estrogen-stimulated breast cancer cell proliferation. Biochem Biophys Res Commun 198:292-297, 1994
Huynh H, Yang X, Pollak M: A role for insulin-like growth factor binding protein 5 in the antiproliferative action of the antiestrogen ICI 182780. Cell Growth Differ 7:1501-1506, 1996
Yee D, Jackson J, Kozelsky T, et al: Insulin-like growth factor binding protein 1 expression inhibits insulin-like growth factor I action in MCF-7 breast cancer cells. Cell Growth Differ 5:73-77, 1994
Gucev Z, Oh Y, Kelley K, et al: Insulin-like growth factor binding protein 3 mediates retinoic acid-and transforming growth factor beta2-induced growth inhibition in human breast cancer cells. Cancer Res 56:1545-1550, 1996
Lee A, Hilsenbeck S, Yee D: IGF system components as prognostic markers in breast cancer. Breast Cancer Res Treat 47:295-302, 1998
Yu H, Levesque M, Clark G, et al: Prognostic value of PSA in breast cancer: A large US cohort study. Proc AACR 38:Abstract #2924, 1997
Yu H, Diamandis E, Levesque M, et al: Prostate specific antigen in breast cancer, benign breast disease and normal breast tissue. Breast Cancer Res Treat 40:171-178, 1996
Rights and permissions
About this article
Cite this article
Ellis, M.J., Jenkins, S., Hanfelt, J. et al. Insulin-like growth factors in human breast cancer. Breast Cancer Res Treat 52, 175–184 (1998). https://doi.org/10.1023/A:1006127621512
Issue Date:
DOI: https://doi.org/10.1023/A:1006127621512