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Regulation of insulin-like growth factors by antiestrogen

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Abstract

Insulin-like growth factors are potent mitogens for breast cancer cell proliferation. This effect is modulated by the cirulatory and extracellular IGFBPs as well as by the affinity of ligand binding receptors on the target cells. Antiestrogens have been shown to reduce both circulatory and microenvironmental IGF levels and thus suppress the IGF-I-induced growth of both ER-positive and ER-negative breast cancer cells. However, the effects of antiestrogens in down regulation of type I IGF receptor and in altering the autophosphorylation tyrosine kinase activity of EGF receptors are mainly observed in ER-positive cells. Furthermore, alteration of IGFBP by antiestrogens such as a marked increase of IGFBP-I production have been shown to inhibit the proliferative effect of IGF-I on ER-positive, but stimulate this effect, on ER-negative cells. Such differential effects from IGF receptor and IGFBP may explain the clinical outcome that tumor regression from antiestrogens is mainly observed in ER-positive type. This assumption based on IGF regulation alone is certainly an oversimplistic view amid the complexity of autocrine, paracrine, and endocrine functions.

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References

  1. O'Brian DA, Liskamp R, Solomon DH, Weinstein IB: Inhibition of protein kinase C by tamoxifen. Cancer Res 45: 2462–2465, 1985

    Google Scholar 

  2. Lam PH-Y: Tamoxifen is a calmodulin antagonist in the activation of cAMP phosphodiesterase. Biochem Biophys Res Comm 118: 27–32, 1984

    Google Scholar 

  3. Thomas T, Trend B, Butterfield JR, Jänne OA, Kiang DT: Regulation of ornithine decarboxylase gene expression in MCF-7 breast cancer cells by antiestrogens. Cancer Res 49: 5852–5887, 1989

    Google Scholar 

  4. Gagliardi A, Collins DC: Inhibition of angiogenesis by antiestrogens. Cancer Res 53: 533–535, 1993

    Google Scholar 

  5. Gloudemans T, Prinsen I, Van Unnik JAM, Lips CJM, Otter WD, Sussenbach JS: Insulin-like growth factor gene expression in human smooth muscle tumors. Cancer Res 50: 6689–6695, 1990

    Google Scholar 

  6. Glick RP, Unterman TG, Van der Woude M, Blaydes LZ: Insulin and insulin-like growth factors in central nervous system tumors. J Neurosurg 77: 445–450, 1992

    Google Scholar 

  7. Lahm H, Suardet L, Laurent PL, Fischer JR, Ceyhan A, Givel JC, Odartchenko N: Growth regulation and co-stimulation of human colorectal cancer cell lines by insulin-like growth factor I, II and transforming growth factor alpha. Br J Cancer 65: 341–346, 1992

    Google Scholar 

  8. Reeve JG, Brinkman A, Hughes S, Mitchell J, Schwander J, Bleehan NM: Expression of insulin-like growth factor (IGF) and IGF-binding protein genes in human lung tumor cell lines. J Natl Cancer Inst 84: 628–634, 1992

    Google Scholar 

  9. Tetenes E, Richard M, Pollak M: Insulin-like growth factor I (IGF-I) responsivity of human melanoma: Potential relevance to activity of tamoxifen (Abstract). Proc Amer Soc Clin Oncol 12: 394, 1993

    Google Scholar 

  10. 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

    Google Scholar 

  11. Osborne CK, Coronado E, Kitten LJ, Arteaga CI, Fuqua SAW, 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

    Google Scholar 

  12. 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

    Google Scholar 

  13. Trojan J, Johnson TR, Rudin SD, Ilan J, Tykocinski ML, Ilan J: Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA. Science 259: 94–97, 1993

    Google Scholar 

  14. Mansfield MJ, Rudlin CR, Crigler JF Jr, Karol KA, Crawford JD, Boepple PA, Crowley WF Jr: Changes in growth and serum growth hormone and plasma somatomedin-C levels during suppression of gonadal sex steroid secretion in girls with central precocious puberty. J Clin Endocrinol Metab 66: 3–9, 1988

    Google Scholar 

  15. Clemmons DR, Underwood LE, Ridgeway EC, Kliman B, Kjelberg RN, Van Wyk JJ: Estradiol treatent of acromegaly: Reduction of immunoreactive somatomedin-C and improvement in metabolic status. Amer J Med 69: 571–575, 1980

    Google Scholar 

  16. Wiedemann E, Schwartz E, Frantz AG: Acute and chronic estrogen effects upon serum somatomedin activity, growth hormone, and prolactin in man. J Clin Endocrinol Metab 42: 942–952, 1976

    Google Scholar 

  17. Copeland KC: Effects of acute high dose and chronic low dose estrogen on plasma somatomedin-C and growth in patients with Turners syndrome. J Clin Endocrinol Metab 66: 1278–1282, 1988

    Google Scholar 

  18. Dawson-Hughes B, Stern D, Goldman J, Reichlin S: Regulation of growth hormone and somatomedin-C secretion in postmenopausal women: Effect of physiological estrogen replacement. J Clin Endocrinol Metab 63: 424–432, 1986

    Google Scholar 

  19. Fröhlander N, von Schoultz B: Growth hormone and somatomedin C during post menopausal replacement therapy with oestrogen alone and in combination with an antioestrogen. Maturitas 9: 297–302, 1988

    Google Scholar 

  20. Ray BS, Pearson OH: Hypophysectomy in treatment of disseminated breast cancer. Surg Clin North Am 42: 419–433, 1962

    Google Scholar 

  21. Jordan VC, Koerner S, Robison C: Inhibition of oestrogen-stimulated prolactin release by anti-oestrogens. J Endocrin 65: 151–152, 1975

    Google Scholar 

  22. Tannenbaum GS, Gurd W, Lapointe M, Pollak M: Tamoxifen attenuates pulsatile growth hormone secretion: Mediation in part by somatostatin. Endocrinology 130: 3395–3401, 1992

    Google Scholar 

  23. Malaab SA, Pollak MN, Goodyer CG: Direct effects of tamoxifen on growth hormone secretion by pituitary cellsin vitro. Eur J Cancer 28A: 788–793, 1992

    Google Scholar 

  24. Colletti RB, Roberts JD, Devlin JT, Copeland KC: Effect of tamoxifen on plasma insulin-like growth factor I in patients with breast cancer. Cancer Res 49: 1882–1884, 1989

    Google Scholar 

  25. Pollak M, Costantino J, Polychronakos C, Blauer SA, Guyda H, Redmond C, Fisher B, Margolese R: Effects of tamoxifen on serum insulin-like growth factor I levels in stage I breast cancer patients. J Natl Cancer Inst 82: 1693–1697, 1990

    Google Scholar 

  26. Kiang DT, Kollander R, Kiang B, Kao PC: Role of plasma IGF-I in endocrine therapy for breast cancer (Abstract). Proc Amer Soc Clin Oncol 11: 51, 1992

    Google Scholar 

  27. Lien EA, Johannessen DC, Aakvaag A, Lønning PE: Influence of tamoxifen, aminoglutethimide and goserelin on human plasma IGF-I levels in breast cancer patients. J Steroid Biochem Mol Biol 41: 541–543, 1992

    Google Scholar 

  28. Furlanetto RW, DiCarlo JN: Somatomedin-C receptors and growth effects in human breast cancer cells maintained in long term tissue culture. Cancer Res 44: 2122–2128, 1984

    Google Scholar 

  29. Myal R, Shiu RPC, Bhaumick B, Bala M: Receptor binding and growth-promoting activity of insulin-like growth factors in human breast cancer cells (T47D) in culture. Cancer Res 44: 5486–5490, 1984

    Google Scholar 

  30. 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

    Google Scholar 

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

    Google Scholar 

  32. Minuto F, Del Monte 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

    Google Scholar 

  33. 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 

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

    Google Scholar 

  35. 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 & Differentiation 2: 457–464, 1991

    Google Scholar 

  36. Arteaga CL, Osborne CK: Growth inhibition of human breast cancer cellsin vitro with an antibody against the type I somatomedin receptor. Cancer Res 49: 6237–6241, 1989

    Google Scholar 

  37. Arteaga CL, Kitten LJ, Coronado EB, Jacobs S, Kull FC Jr, Allred DC, Osborne CK: Blockage of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 84: 1418–1423, 1989

    Google Scholar 

  38. Peyrat J-P, Bonneterre J, Beuscart R, Djiane J, Demaille A: Insulin-like growth factor I receptors in human breast cancer and their relation to estradiol and progesterone receptors. Cancer Res 48: 6429–6433, 1988

    Google Scholar 

  39. Pekonen F, Partanen S, Mäkinen T, Rutanan E-M: Receptors for epidermal growth factor and insulin-like growth factor I and their relation to steroid receptors in human breast cancer. Cancer Res 48: 1343–1347, 1988

    Google Scholar 

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

    Google Scholar 

  41. Chen J-C, Shao Z-M, Sheikh MS, Hussain A, LeRoith D, Roberts CT Jr, Fontana JA: Insulin-like growth factor-binding protein-3 enhancement of DNA synthesis in breast carcinoma cells (Abstract). Proc Amer Assoc Cancer Res 34: 238, 1993

    Google Scholar 

  42. Sheikh MS, Shao ZM, Clemmons DR, LeRoith D, Roberts CT Jr, Fontana JA: Identification of the insulin-like growth factor binding proteins 5 and 6 (IGFBP-5 and 6) in human breast cancer cells. Biochem Biophys Res Comm 183: 1003–1010, 1992

    Google Scholar 

  43. Huff KK, Knabbe C, Lindsey R, Kaufman D, Bronzert D, Lippman ME, Dickson RB: Multihormonal regulation of insulin-like growth factor-I-related protein in MCF-7 human breast cancer cells. Mol Endocrinol 2: 200–208, 1988

    Google Scholar 

  44. Cullen KJ, Yee D, Bates SE, Brunner N, Clarke R, Dickson RE, Huff KK, Paik S, Rosen N, Valverius E, Zugmaier G, Lippman ME: Regulation of human breast cancer by secreted growth factors. Acta Oncologica 28: 835–839, 1989

    Google Scholar 

  45. Brünner N, Zugmaier G, Bano M, Ennis BW, Clarke R, Cullen KJ, Kern FC, Dickson RB, Lippman ME: Endocrine therapy of human breast cancer cells: The role of secreted polypeptide growth factors. Cancer Cells 1: 81–86, 1989

    Google Scholar 

  46. Van der Burg B, Rutteman GR, Blankenstein MA, De Laat SW, Van Zoelen EJJ: Mitogenic stimulation of human breast cancer cells in a growth factor-defined medium: Synergistic action of insulin and estrogen. J Cell Physiol 134: 101–108, 1988

    Google Scholar 

  47. Wakeling AE: Comparative studies on the effects of steroidal and nonsteroidal oestrogen antagonists on the proliferation of human breast cancer cells. J Steroid Biochem 34: 183–188, 1989

    Google Scholar 

  48. Vignon F, Bouton M-M, Rochefort H: Antiestrogens inhibit the mitogenic effect of growth factors on breast cancer cells in the total absence of estrogens. Biochem Biophys Res Comm 146: 1502–1508, 1987

    Google Scholar 

  49. 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

    Google Scholar 

  50. Manni A, Wright C, Buck H: Growth factor involvement in the multihormonal regulation of MCF-7 breast cancer cell growth in soft agar. Breast Cancer Res Treat 20: 43–52, 1991

    Google Scholar 

  51. 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 265: 21172–21178, 1990

    Google Scholar 

  52. Freiss G, Rochefort H, Vignon F: Mechanisms of 4-hydroxytamoxifen anti-growth factor activity in breast cancer cells: Alterations of growth factor receptor binding sites and tyrosine kinase activity. Biochem Biophys Res Comm 173: 919–926, 1990

    Google Scholar 

  53. Baxter RC, Martin JL: Radioimmunoassay of growth hormone-dependent insulin-like growth factor binding protein in human plasma. J Clin Invest 78: 1504–1512, 1986

    Google Scholar 

  54. Hill DJ, Camacho-Hubner C, Rashid P, Strain AJ, Clemmons DR: Insulin-like growth factor (IGF)-binding protein release by human fetal fibroblasts: Dependency on cell density and IGF peptides. J Endocrinol 122: 87–98, 1989

    Google Scholar 

  55. McGuire WL Jr, Jackson JG, Figueroa JA, Shimasaki S, Powell DR, Yee D: Regulation of insulin-like growth factorbinding protein (IGFBP) expression by breast cancer cells: Use of IGFBP-1 as an inhibitor of insulin-like growth factor action. J Natl Cancer Inst 84: 1336–1341, 1992

    Google Scholar 

  56. Figueroa JA, Sharma J, Jackson JG, McDermott MJ, Yee D: Recombinant insulin-like growth factor binding protein-1 (rBP-1) inhibits breast cancer cell growthin vitro (Abstract). Proc Amer Assn Cancer Res 34: 246, 1993

    Google Scholar 

  57. Lønning PE, Hall K, Aakvaag A, Lien EA: Influence of tamoxifen on plasma levels of insulin-like growth factor I and insulin-like growth factor binding protein I in breast cancer patients. Cancer Res 52: 4719–4723, 1992

    Google Scholar 

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

    Google Scholar 

  59. Coutts A, Murphy LJ, Murphy LC: Regulation of IGF-binding proteins by progestins and antiestrogens in T-47D human breast cancer cells (Abstract). Proc Amer Assn Cancer Res 34: 93, 1993

    Google Scholar 

  60. Kerbel RS: Expression of multi-cytokine resistance and multi-growth factor independence in advanced stage metastatic cancer: Malignant melanoma as a paradigm. Am J Pathol 141: 519–524, 1992

    Google Scholar 

  61. Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottigi R, Papadia F, Sofra MC, Bacchi M: Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med 327: 516–523, 1992

    Google Scholar 

  62. Copeland KC, Underwood LE, Van Wyk JJ: Induction of immunoreactive somatomedin C in human serum by growth hormone: Dose-response relationships and effects on chromatographic profile. J Clin Endocrinol Metab 50: 690–697, 1980

    Google Scholar 

  63. Vennin PH, Peyrat JP, Bonneterre J, Louchez MM, Harris AG, Demaille A: Effect of the long-acting somatostatin analogue SMS 201-995 (Sandostatin) in advanced breast cancer. Anticancer Res 9: 153–156, 1989

    Google Scholar 

  64. Weber C, Merriam L, Koschitzky T, Karp F, Benson M, Forde K, LoGerfo P: Inhibition of growth of human breast carcinomasin vivo by somatostain analog SMS 201-995: Treatment of nude mouse xenografts. Surgery 106: 416–422, 1989

    Google Scholar 

  65. Hung H, Pollak M: Synergistic reduction of expression of the IGF-I gene by the combination of somatostain and tamoxifen (Abstract). Proc Amer Assn Cancer Res 12: 121, 1993

    Google Scholar 

  66. Kao PC, Tateishi K, Abboud CF, Zimmerman D, Randall RV, Li CH: Assay of somatomedin C by cartridge extraction prior to radioimmunoassay with antiserum developed against synthetic somatomedin C. Annal Clin Lab Sci 18: 120–130, 1988

    Google Scholar 

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Winston, R., Kao, P.C. & Kiang, D.T. Regulation of insulin-like growth factors by antiestrogen. Breast Cancer Res Tr 31, 107–115 (1994). https://doi.org/10.1007/BF00689681

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