Breast Cancer Research and Treatment

, Volume 31, Issue 1, pp 5–9

Alternative mechanisms of action of anti-oestrogens

  • Anthony A. Colletta
  • John R. Benson
  • Michael Baum
Article

Summary

The molecular mechanism of action of anti-oestrogens such as tamoxifen appears to be a complex mixture of antagonism of the mitogenic action of oestradiol at the level of the oestrogen receptor, plus a range of other activities from enzyme inhibition to growth factor modulation. This article will concentrate on two specific areas: 1) the inhibition of protein kinase C and calmodulin-dependent cAMP phosphodiesterase; and 2) the regulation by tamoxifen of peptide regulators of breast cancer epithelial cell growth such as insulin-like growth factor I (IGF I) and transforming growth factor beta (TGF-β). The elucidation of these mechanisms is potentially important in the treatment and chemoprevention of breast cancer — the quantitative contribution of each individual mechanism of the overall antineoplastic action of anti-oestrogens is central to developing new and possibly more effective anti-oestrogens and optimizing strategies for their use.

Key words

antiestrogens cAMP phosphodiesterase growth factors insulin-like growth factors protein kinase C tamoxifen transforming growth factor beta 

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References

  1. 1.
    Evans RM: The steroid and thyroid hormone receptor superfamily. Science 240: 889–895, 1988Google Scholar
  2. 2.
    Ham J, Parker MG: Regulation of gene expression by nuclear hormone receptors. Curr Opinion Cell Biol 1: 503–511, 1989Google Scholar
  3. 3.
    Green S, Chambon P: Nuclear receptors enhance our understanding of transcriptional regulation. Trends Genet 4: 309–314, 1988Google Scholar
  4. 4.
    Coezy E, Borgna JL, Rochefort H: Tamoxifen and metabolites in MCF-7 cells: correlation between binding to oestrogen receptor and inhibition of cell growth. Cancer Res 42: 317–323, 1982Google Scholar
  5. 5.
    Green S, Chambon P: The oestrogen receptor: from perception to mechanism. In: Parker MG (ed) Nuclear Hormone Receptors 2. Academic Press, London, 1991, pp 15–34Google Scholar
  6. 6.
    Sutherland RL, Hall RE, Taylor IW: Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effect of tamoxifen on exponentially growing and plateau phase cells. Cancer Res 43: 3998–4006, 1983Google Scholar
  7. 7.
    Sutherland RL, Watts CKW, Reunitz PC: Definition of two distinct mechanisms of action of antioestrogens on human breast cancer cell proliferation using hydroxytriphenylethylenes with high affinity for the oestrogen receptor. Biochem Biophys Res Comm 140: 523–529, 1986Google Scholar
  8. 8.
    Sutherland RL, Murphy LC, Ming San Foo, Green MD, Whybourne AN: High affinity anti-oestrogen binding site distinct from the oestrogen receptor. Nature 288: 273–275, 1980Google Scholar
  9. 9.
    O'Brian CA, Liskamp RM, Solomon DH, Weinstein IB: Inhibition of protein kinase C by tamoxifen. Cancer Res 45: 2462–2465, 1985Google Scholar
  10. 10.
    Berridge MJ, Irving RF: Inositol triphosphate, a novel second messenger in cellular signal transduction. Nature 312: 315–321, 1984Google Scholar
  11. 11.
    O'Brian CA, Liskamp RM, Solomon DH, Weinstein IB: Triphenylethylenes: A new class of Protein Kinase C inhibitors. J Natl Cancer Inst 76: 1243–1246, 1986Google Scholar
  12. 12.
    Su H-D, Mazzei GJ, Vogler WR, Kuo JF: Effect of tamoxifen, a non-steroidal antioestrogen, on phospholipid/calcium dependent protein kinase and phosphorylation of its endogenous substrate proteins from the rat brain ovary. Biochem Pharmacol 34: 3649–3653, 1985Google Scholar
  13. 13.
    Lam H-YP: Tamoxifen is a calmodulin antagonist in the activation of a cAMP phosphodiesterase. Biochem Biophys Res Comm 118: 27–32, 1984Google Scholar
  14. 14.
    Rowland MG, Parr IB, MacCague R, Jarman M, Goddard PM: Variation of the inhibition of calmodulin dependent cyclic AMP phospho-diesterase among analogues of tamoxifen: Correlation with cytotoxicity. Biochem Pharmacol 40: 283–289, 1990Google Scholar
  15. 15.
    Gulino A, Barrera G, Vacca A, Farina Aet al.: Calmodulin antagonism and growth inhibitory activity of triphenylethylene antioestrogens in MCF-7 human breast cancer cells. Cancer Res 46: 6274–6278, 1986Google Scholar
  16. 16.
    Musgrove EA, Wakeling AE, Sutherland RL: Points of action of oestrogen antagonists and a calmodulin antagonist within the MCF-7 human breast cancer cell cycle. Cancer Res 49: 2398–2404, 1989Google Scholar
  17. 17.
    Nolvadex Adjuvant Trial Organisation: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Br J Cancer 54: 608–611, 1987Google Scholar
  18. 18.
    Medical Research Council Scottish Trials Office: Adjuvant tamoxifen in the management of operable breast cancer. Lancet ii: 171–175, 1988Google Scholar
  19. 19.
    Early Breast Cancer Trialists Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339: 1–15 and 71-75, 1992Google Scholar
  20. 20.
    Brooks MD, Ebbs SR, Colletta AA, Baum M: Desmoid tumours treated with triphenylethylenes. Eur J Cancer 28: 1014–1018, 1992Google Scholar
  21. 21.
    Colletta AA, Wakefield LM, Howell FV, Roozendaal KEP, Danielpour D, Ebbs SR, Sporn MB, Baum M: Anti-oestrogens induce the secretion of active transforming growth factor beta from human foetal fibroblasts. Br J Cancer 62:405–409, 1990Google Scholar
  22. 22.
    Haggie JA, Sellwood RA, Howell A, Birch JM, Schor SL: Fibroblasts from relatives of patients with hereditary breast cancer show foetal-like behaviourin vitro. Lancet i: 1455–1457, 1987Google Scholar
  23. 23.
    Shor SL, Haggie JA, Durning P, Howell A, Smith L, Sellwood RA, Crowther D: Occurrence of a foetal fibroblast phenotype in familial breast cancer. Int J Cancer 37: 831–836, 1986Google Scholar
  24. 24.
    Glick AB, Danielpour D, Morgan D, Sporn MB, Yuspa SH: Induction and autocrine receptor binding of TGF-β2 during terminal differentiation of primary mouse keratinocytes. Mol Endocrinology 4: 46–52, 1990Google Scholar
  25. 25.
    Knabbe C, Lippman ME, Wakefield LM, Flanders KC, Kasid A, Derynck R, Dickson RB: Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer. Cell 48: 417–428, 1987Google Scholar
  26. 26.
    Colletta AA, Wakefield LM, Howell FV, Danielpour D, Baum M, Sporn MB: The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta. J Clin Invest 87: 277–283, 1991Google Scholar
  27. 27.
    Butta A, MacLennan K, Flanders KC, Sacks NPM, Smith I, MacKinna A, Dowsett M, Wakefield LM, Sporn MB, Baum M, Colletta AA: Induction of transforming growth factor beta in human breast cancerin vivo following tamoxifen treatment. Cancer Res 52: 4261–4262, 1992Google Scholar
  28. 28.
    Mansi JL, Smith IE, Walsh G, A'Hern RP, Harmer C, Sinnett HD, Trott PA, Fisher C, McKinna JA: Primary medical therapy for operable breast cancer. Eur J Clin Oncol 25: 1623–1627, 1989Google Scholar
  29. 29.
    Myall Y, Shiu RPC, Bhaumick B: Receptor binding and growth promoting activity of insulin-like growth factors in human breast cancer cells (T47D) in culture. Cancer Res 44: 5486–5490, 1984Google Scholar
  30. 30.
    Karey KP, Sirbasku DA: Differential responsiveness of human breast cancer cell lines MCF-7 and T47D to growth factors and 17β-oestradiol. Cancer Res 48: 4083–4092, 1988Google Scholar
  31. 31.
    Cullen KJ, Lippman ME, Chow D, Hill S, Rosen N, Zwiebel JA: Insulin-like growth factor-II over-expression in MCF-7 cells induces phenotypic changes associated with malignant progression. Mol Endocrinology 6: 91–100, 1992Google Scholar
  32. 32.
    Cullen KJ, Yee D, Sly WSet al.: Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50: 48–53, 1990Google Scholar
  33. 33.
    Pekonen F, Paranen S, Makinen T, Rutanen 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, 1988Google Scholar
  34. 34.
    Peyrat JP, Bonneterre J, Beuscart R, Djianne J, Demaille A: Insulin-like growth factor I receptors in human breast cancer and their relation to oestradiol and progesterone receptors. Cancer Res 48: 6429–6433, 1988Google Scholar
  35. 35.
    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, 1988Google Scholar
  36. 36.
    Yee D, Paik S, Lebovic G, Marcus R, Favoni R, 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, 1989Google Scholar
  37. 37.
    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, 1991Google Scholar
  38. 38.
    Pollak M, Huynh HT, Pratt Lefebvre S: Tamoxifen reduces serum insulin-like growth factor I (IGF I). Breast Cancer Research and Treatment 22: 91–100, 1992Google Scholar
  39. 39.
    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 Comm 153: 1076–1083, 1988Google Scholar
  40. 40.
    Pollak M, Sem AW, Richard M, Tetenes E, Bell R: Inhibition of metastatic behaviour of murine osteosarcoma by hypophysectomy. J Natl Cancer Inst 84: 966–971, 1992Google Scholar
  41. 41.
    Tannenbaum GS, Gurd W, Lapointe M, Pollak M: Tamoxifen attenuates pulsatile growth hormone secretion: Mediated in part by somatostatin. Endocrinology 130: 3395–3402, 1992Google Scholar
  42. 42.
    Huynh HT, Tetenes E, Wallace L, Pollak M:In vivo inhibition of insulin-like growth factor I gene expression by tamoxifen. Cancer Res 53: 1727–1730, 1993Google Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Anthony A. Colletta
    • 1
  • John R. Benson
    • 1
  • Michael Baum
    • 1
  1. 1.Section of Academic SurgeryInstitute of Cancer Research, Royal Marsden HospitalLondonUK

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