Summary
Several protooncogenes and suppressor genes and a variety of growth factors and their receptors have been shown to be mutated, deleted, or activated in human breast cancer. These changes may account for the unregulated growth of breast carcinoma cells.
Insulin-like growth factors I and II (IGF-I, IGF-II) belong to a family of polypeptides with growth promoting properties and structural homology to insulin. They exert their mitogenic effects by binding to the IGF-I receptor and activating its tyrosine protein kinase. Other proteins that specifically bind the IGFs include the plasma membrane IGF-II receptor, which also binds lysosomal hydrolases, and several IGF-binding proteins which may serve to modulate IGF interactions with receptors.
Breast cancer cell lines express IGF-I and IGF-II receptors and different patterns of binding proteins. IGF-I and IGF-II are each mitogenic for subsets of breast cancer cell lines. This effect is inhibited by antibodies directed against the IGF-I receptor. In breast tumors, IGF-I is expressed by stromal cells, but not carcinoma cells; it is not expressed by breast cancer cell lines. IGF-I is therefore a potential paracrine regulator of breast cancer cell growth. Similarly, IGF-II is expressed in breast tumors, predominantly in stromal cells, but sometimes also in carcinoma cells and in a subset of cell lines. Thus, IGF-II is also a potential paracrine regulator of breast cancer cell growth; in addition, it can be an autocrine regulator in some breast cancer cells.
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References
WHO IARC: Cancer Incidence in Five Continents, vol 5. Muir C, Waterhouse J, Mack T,et al. (eds): Lyon, IARC Sci Publ 88, 1987, p 882
Haenszel L, Kurihara M: Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. JNCI 40: 43, 1968
Muir C, Malhotra A: In: Changing Cancer Patterns and Topics in Cancer Epidemiology (Kurihara M, ed) Gann. Monograph No. 33, Plenum Press, NY, 1987
Henderson BE: Endogenous and exogenous endocrine factors. In: Diagnosis and Therapy of Breast Cancer. Hematology/Oncology Clinics of North America 3: 577–598, 1989
Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Westin A, Modali R, Harris CC, Vogelstein B: Mutations of the p53 gene occur in diverse tumor types. Nature 342: 705–708, 1989
Callahan R, Campbell G: Mutations in human breast cancer: an overview. JNCI 81: 1780–1787, 1989
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MJ: Studies of the HER-2/neu protooncogene in human breast and ovarian cancer. Science 244: 621–624, 1989
Hudziak RM, Schlessinger J, Ullrich A: Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH3T3 cells. Proc Natl Acad Sci USA 84: 7159–7162, 1987
Sporn MB, Roberts AB: Peptide growth factors and inflammation, tissue repair and cancer. J Clin Invest 78: 329–332, 1986
Clarke R, Brunner N, Katz D, Glenz P, Dickson RB, Lippman ME, Kern F: The effects of a constituitive production of TGF-α on the growth of MCF-7 human breast cancer cellsin vitro andin vivo. Mol Endocrinol 3: 372–380, 1989
Ennis BW, Valverius EM, Lippman ME, Bellot F, Kris R, Schlessinger J, Masui H, Goldberg A, Mendelsohn J, Dickson RB: Anti-EGF receptor antibodies inhibit the autocrine stimulated growth of MDA-MB-468 breast cancer cells. Mol Endocrinol 3: 1830–1838, 1989
Knabbe C, Wakefield L, Flanders K, Kasid A, Derynck R, Lippman ME, Dickson RB: Evidence that TGF-beta is a hormonally regulated negative growth factor in human breast cancer. Cell 48: 417–428, 1987
Bates SE, McManaway ME, Lippman ME, Dickson RB: Characterization of estrogen responsive transforming activity in human breast cancer cell lines. Cancer Res 46: 1707–1713, 1986
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: 5762–5767, 1987
Wellstein A, Lippman ME: Fibroblast growth factors and breast cancer. In: Broder S (ed) Molecular Foundation of Oncology. Williams and Wilkins, Baltimore, 1990. In press
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
Nissley SP, Rechler MM: Insulin-like growth factors: biosynthesis receptors and carrier proteins. Hormonal Proteins and Peptides 12: 127–203, 1986
Baxter RC: The somatomedins: Insulin-like growth factors. Adv Clin Chem 25: 49–115, 1986
Czech MP: Structural and functional homologies in the receptors for insulin and the insulin-like growth factors. Cell 31: 8–10, 1982
Lammers R, Gray A, Schlessinger J, Ullrich A: Differential signalling potential of insulin- and IGF-I receptor cytoplasmic domains. EMBO J 8: 1369–1375, 1989
Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, Rutter WJ: Insulin-like growth factor II receptor as a multifunctional binding protein. Nature (London) 329: 301–307, 1987
Lobel P, Dahms NM, Breitmeyer J, Chirgwin JM, Kornfeld S: Cloning of the bovine 215 kDa cation-independent mannose-6-phosphate receptor. Proc Natl Acad Sci USA 84: 2233–2237, 1987
Czech MP, Lewis RE, Corvera S: Multifunctional glycoprotein receptors for insulin and the insulin-like growth factors. CIBA Found Symp 145: 27–44, 1989
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
Barnes D, Sato G: Serum-free cell culture: a unifying approach. Cell 22: 649–655, 1980
Gai X, Rizzo MG, Lee J, Ullrich A, Baserga R: Abrogation of the requirements for added growth factors in 3T3 cells constitutively expressing the p53 and IGF-I genes. Oncogene Res 3: 377–386, 1988
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
Karey KP, Sirbasku D: A differential responsiveness of human breast cancer cell lines MCF-7 and T47-D to growth factors and 17-B estradiol. Cancer Res 48: 4083–4092, 1988
Furlanetto RW, DeCarlo JN: Somatomedin-C receptors and growth effects in human breast cells maintained in long term tissue culture. Cancer Res 44: 2122–2128, 1984
DeLeon 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
Huff KK, Kaufman D, Gabbay KJ, Spencer EM, Lippman ME, Dickson RB: Human breast cancer cells secrete an insulin-like growth factor I-related polypeptide. Cancer Res 46: 4613–4619, 1986
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
Pollack MN, Perdue JF, Margolese RG,et al.: Presence of somatomedin receptors on human breast and colon carcinomas. Cancer Lett 38: 223–230, 1987
Peyrat JP, Bonneterre J, Laurent JC,et al.: Presence and characterization of insulin-like growth factor 1 receptors in human benign breast disease. Eur J Cancer Clin Oncol 24: 1425–1431, 1988
Baxter RC: The somatomedins: insulin-like growth factors. Adv Clin Chem 25: 49–115, 1986
Foekens JA, Portengen M, Janssen M, Klijn JGM: Insulin-like growth factor I receptors and insulin-like growth factor I activity in primary human breast cancer. Cancer 63: 2139–2147, 1989
Minuto F, DelMonte P, Barreca A, Nicolin A, Giordano G: Partial characterization of somatomedin C-like immunoreactivity secreted by breast cancer cellsin vitro. Mol Cell Endocrinol 54: 179–184, 1987
Ahmed ST, Manni A, Gray G, Hammond J: Hormonal regulation and characterization of radioimmunoassayable insulin-like growth factor I activity secreted by human breast cancer cells. Proc Amer Assoc Cancer Res 30: A1162, 1989
Yee D, Paik S, Lebovic GS, Marcus RR, Favoni RE, Cullen KJ, Lippman ME, Rosen N: Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol Endocrinol 3: 509–517, 1989
Binoux M, Hossenlopp P, Harouin S, Seurin D, Lassarre C, Gourmelen M: Somatomedin (insulin-like growth factors)-binding proteins, molecular forms and regulation. Hormone Res 24: 141–151, 1986
Daughaday WH, Kapadia M, Mariz A: Serum somatomedin binding proteins: physiologic significance and interference in radioligand assay. J Lab Clin Med 109: 355, 1987
Lee YL, 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
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
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
DeLeon DD, Wilson DM, Bakker B, Lamsom G, Hintz RL, Rosenfeld RG: Characterization of insulin-like growth factor (IGF) binding proteins from human breast cancer cells. Mol Endocrinol 3: 567–574, 1989
Peres R, Betsholtz C, Westermark B, Heldin CH: Frequent expression of growth factors for mesenchymal cells in human mammary carcinoma cell lines. Cancer Res 47: 3425–3429, 1987
Arteaga CL, Kitten L, Coronado E, Jacobs S, Kull F, 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
Cullen KJ, Hill S, Paik S, Smith HS, Lippman ME, Rosen N: Growth factor mRNA expression by human breast fibroblasts from benign and malignant lesions. Proc Am Assoc Cancer Res 31: A1275, 1990
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Rosen, N., Yee, D., Lippman, M.E. et al. Insulin-like growth factors in human breast cancer. Breast Cancer Res Tr 18 (Suppl 1), S55–S62 (1991). https://doi.org/10.1007/BF02633529
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DOI: https://doi.org/10.1007/BF02633529