Summary
The insulin-like growth factors (IGFs) are mitogens for many cancer cell types. In breast cancer cells, IGF-I and IGF-II have both been shown to stimulate cell proliferation. However, IGF-I mRNA has not been found in human breast cancer cell lines, making it unlikely that IGF-I is commonly expressed as an autocrine growth factor for breast cancer cells. Nevertheless, IGF-I mRNA can be detected in breast cancer tissue samples, and in situ hybridization studies have shown that the message originates from the stromal cells adjacent to normal lobules. IGF-II, on the other hand, has been detected in some breast cancer cell lines. In the estrogen receptor positive cell line T47-D, IGF-II mRNA was induced by estradiol. Furthermore, transfection of an IGF-II expression vector into a previously estrogen-dependent cell line resulted in hormone independent growth. Thus, IGF-II can be expressed as an autocrine growth factor in some breast cancers and its expression may, in part, result in hormone independence. Finally, stromal cells obtained from breast tissues showed that IGF-I was commonly expressed in fibroblasts derived from non-malignant biopsy specimens, while IGF-II mRNA was detected in fibroblasts adjacent to malignant tissue. These studies suggest that IGF-II expression may be important in both autocrine and paracrine regulation of breast cancer cell growth.
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References
Reeve AE, Eccles MR, Wilkiens RJ: Expression of insulin-like growth factor II transcripts in Wilms' tumor. Nature 317:258–260, 1985
Scott J, Cowell J, Robertson ME: Insulin-like growth factor II gene expression in Wilms' tumor and embryonic tissues. Nature 317:260–262, 1985
Haselbacher GK, Irminger J-C, Zapf J, Ziegler WH, Humbel RE: Insulin-like growth factor II in human adrenal pheochromocytomas and Wilms' tumors: expression at the mRNA and protein level. Proc Natl Acad Sci USA 84:1104–1106, 1987
Paik S, Rosen N, Jung W, You JM, Lippman ME, Perdue JF, Yee D: Expression of insulin-like growth factor-II mRNA in fetal kidney and Wilms' tumor. Lab Invest 61:522–526, 1989
Pavelic K, Vrbanec D, Marusic S, Levanat S, Cabrijan T: Autocrine tumor growth regulation by somatomedin C: an in-vitro model. J Endocrinol 109:233–238, 1986
El-Badry OM, Minniti C, Kohn EC, Houghton PJ, Daughaday WH, Helman LJ: Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors. Cell Growth and Differentiation 1:325–331, 1990
Yee D, Favoni RE, Lebovic GS, Lombana F, Powell DR, Reynolds CP, Rosen N: Insulin-like growth factor I expression of tumors of neuroectodermal origin with the t(11;22) chromosomal translocation. J Clin Invest 86:1806–1814, 1990
Ueno T, Takahashi K, Matsuguchi T, Endo H, Yamamoto M: Transcriptional deviation of the rat insulin-like growth factor gene initiated at three alternative leader-exons between neonatal tissues and ascites hepatomas. Biochim Biophys Acta 950:411–419, 1988
Su T-S, Liu W-Y, Han S-H, Jansen M, Yang-Fen TL, P'eng F-K, Chou C-K: Transcripts of the insulin-like growth factors I and II in human hepatoma. Cancer Res 49:1773–1777, 1989
Yang DY, Rogler CE: Analysis of insulin-like growth factor II expression in neoplastic nodules and hepatocellular carcinomas of woodchucks utilizing in situ hybridization and immunocytochemistry. Carcinogenesis 12:1893–1901, 1991
Minuto F, Del Monte P, Barreca A: Evidence for increased somatomedin-C/insulin-like growth factor content in primary human lung tumors. Cancer Res 46:985–988, 1986
Nakaanishi Y, Mulshine J, Kasprzyk PG: Insulin-like growth factor I can mediate autocrine proliferation of small cell lung cancer cell lines in vitro. J Clin Invest 82:354–359, 1988
Tricoli JV, Rall LB, Karakousis CP: Enhanced levels of insulin-like growth factor messenger RNA in human colon carcinomas and liposarcomas. Cancer Res 46:6169–6173, 1986
Yee D, Morales FR, Hamilton TC, Von Hoff DD: Expression of insulin-like growth factor I, its binding proteins, and its receptor in ovarian cancer. Cancer Res 51:5107–5112, 1991
Pollak MN, Polychronakos C, Richard M: Insulin-like growth factor I: a potent mitogen for human osteogenic sarcoma. JNCI 82:301–305, 1990
Ohmura E, Okada M, Onoda N, Kamiya Y, Murakami H, Tsushima T, Shizume K: Insulin-like growth factor I and transforming growth factor α as autocrine growth factors in human pancreatic cancer cell growth. Cancer Res 50:103–107, 1990
Neely EK, Morhenn VB, Hintz RL, Wilson DM, Rosenfeld RG: Insulin-like growth factors are mitogenic for human keratinocytes and a squamous cell carcinoma. J Invest Dermatol 96:104–110, 1991
Flier JS, Usher P, Moses AC: Monoclonal antibody to the type I insulin-like growth factor receptor blocks IGF-I receptor mediated DNA synthesis: Clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts. Proc Natl Acad Sci USA 83:664–668, 1986
Kaleko M, Rutter WJ, Miller AD: Overexpression of the human insulin-like growth factor I receptor promotes ligand dependent neoplastic transformation. Mol Cell Biol 10:464–473, 1990
Furlanetto RW, DiCarlo JN: Somatomedin-C receptors and growth effects in human breast cells maintained in long term tissue culture. Cancer Res 44: 2122–2128, 1984
Karey KP, Sirbasku DA: Differential responsiveness of human breast cancer cell lines MCF-7 and T47D to growth factors and 17β-estradiol. Cancer Res 48:4083–4092, 1988
Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, Lippman ME, Rosen N: Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50:48–53, 1990
Shamay A, Cohen N, Niwa M, Gertler A: Effect of insulin-like growth factor I on deoxyribonucleic acid synthesis and galactopoiesis in bovine undifferentiated and lactating mammary tissuein vitro. Endocrinology 123:804–809, 1988
Wakeling AE, Newboult E, Peters SW: Effects of antioestrogens on the proliferation of MCF-7 human breast cancer cells. J Mol Endocrinol 2: 225–234, 1989
Stewart AJ, Johnson MD, May FEB, Westley BR: Role of insulin like growth factor receptors in the estrogen stimulated proliferation of human breast cancer cells. J Biol Chem 265:21172–21178, 1990
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
Osborne CK, Coronado EB, Kitten LJ, Arteaga CL, Fuqua SA, Ramasharma K, Marshall 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
Fradkin JE, Easman RC, Lesniak MA, Roth J: Specificity spillover at the hormone receptor — exploring its role in human disease. N Engl J Med 320:640–645, 1989
Beukers MW, Youngman O, Zhang H, Ling N, Rosenfeld RG: Leu27 insulin-like growth factor II is highly selective for the type II IGF receptor in binding, cross linking, and thymidine incorporation experiments. Endocrinology 128:1201–1203, 1991
Stracke ML, Kohn EC, Aznavoorian SA, Wilson LL, Salomon D, Krutzsch HC, Liotta LA, Schiffmann E: Insulin-like growth factors stimulate chemotaxis in human melanoma cells. Biochem Biophys Res Commun 153:1076–1083, 1988
Stracke ML, Engel JD, Wilson LW, Rechler MM, Liotta LA, Schiffmann E: The type I insulin-like growth factor receptor is a motility receptor in human melanoma cells. J Biol Chem 264:21544–21549, 1989
Kohn EC, Francis EA, Liotta LA, Schiffmann E: Heterogeneity of the motility responses in malignant tumor cells: a biological basis for the diversity and homing of metastatic cells. Int J Cancer 46:287–292, 1990
El-Badry OM, Minniti C, Kohn EC, Houghton PJ, Daughaday WH, Helman LJ: Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors. Cell Growth Differen 1:325–331, 1990
Huff KK, Kaufman D, Gabbay KH: Secretion of an insulin-like growth factor-I-related protein by human breast cancer cells. Cancer Res 46:4613–4619, 1986
Minuto F, DelMonte P, Barreca A: Partial characterization of somatomedin C-like immunoreactivity secreted by breast cancer cells in vitro. Mol Cell Endocrinol 54:179–184, 1987
Karey KP, Sirbasku DA: Differential responsiveness of human breast cancer cell lines MCF-7 and T47D to growth factors and 17β-estradiol. Cancer Res 48:4083–4092, 1988
Ahmed ST, Manni A, Gray G: Hormonal regulation and characterization of radioimmunoassayable insulin like growth factor I activity secreted by human breast cancer cells. Proc AACR 30:A11
Yee D, Paik S, Lebovic GS, Marcus RR, Favoni 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
Tobin G, Yee D, Brunner N, Rotwein P: A novel insulin-like growth factor I messenger RNA is expressed in normal and tumor cells. Mol Endocrinol 4:1914–1920, 1990
Ogasawara M, Karey KP, Sirbasku DA: Insulin-like growth factor I: relationship between plasma and tissue sources, biological potency, and N-alpha truncation. Proc AACR 29:A207, 1988
Rohlik QT, Adams B, Kull FC, Jacobs S: An antibody to the receptor for insulin-like growth factor I inhibits the growth of MCF-7 cells in tissue culture. Biochem Biophys Res Commun 149:276–281, 1987
Arteaga CL, Kitten LJ, Coronado EB, Jacobs S, Kull FC, Allred DC, Osborne CK: Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 84:1418–1423, 1989
Yee D, Cullen KJ, Paik S, Perdue JF, Lippman ME, Rosen N: Insulin-like growth factor II expresion in human breast cancer. Cancer Res 48:6691–6696, 1988
Brunner N, Yee D, Kern FG, Spang-Thomsen M, Lippman ME, Cullen KJ: Effect of endocrine therapy on growth of T61 human breast cancer xenografts is directly correlated to a specific down-regulation of insulin-like growth factor II. (Submitted.)
Cullen KJ, Lippman ME, Chow D, Hill S, Rosen N, Zwiebel J: IGF-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression. Mol Endocrinol 6:91–100, 1992
Daly RJ, Haris 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 cell. Cell Growth Differen 2:457–464, 1991
Cullen KJ, Smith HS, Hill S, Rosen N, Lippman ME: Growth factor mRNA expression by human breast fibroblasts from benign and malignant tissues. Cancer Res 51:4978–4985, 1991
Tucker RF, Shipley GD, Moses HL, Holley RW: Growth inhibitor from BSC-I cells closely related to platelet type beta transforming growth factor. Science 226:705–707, 1984
Roberts AB, Anzano MA, Wakefield LM, Roche NS, Stern DF, Sporn MB: Type one beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci USA 82:119–123, 1985
Bronzert DA, Pantazis P, Antoniades HN, Kasid A, Davidson N, Dickson RB, Lippman ME: Synthesis and secretion of platelet derived growth factor by human breast cancer cell lines. Proc Natl Acad Sci USA 84:5763–5767, 1987
Nonomura N, Lu J, Tanaka A, Yamanishi H, Sato B, Sonoda T, Matsumoto K: Interaction of androgen induced autocrine heparin-binding growth factor with fibroblast growth factor receptor on androgen-dependent Shionogi carcinoma 115 cells. Cancer Res 50:2316–2321, 1990
Singer C, Smith HS, Lippman ME, Cullen KJ: IGF-I and IGF-II expression in fibroblasts derived from tumor, normal breast, and skin of breast cancer patients. Proc AACR 33:A1612, 1992
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Cullen, K.J., Allison, A., Martire, I. et al. Insulin-like growth factor expression in breast cancer epithelium and stroma. Breast Cancer Res Tr 22, 21–29 (1992). https://doi.org/10.1007/BF01833330
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DOI: https://doi.org/10.1007/BF01833330