Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Chemoprevention of breast cancer with selective oestrogen-receptor modulators

Abstract

Twenty years ago, a new therapeutic dimension was conceived that not only had the potential to treat and prevent osteoporosis, but to prevent breast and endometrial cancer at the same time. As osteoporosis was known to be caused by oestrogen withdrawal after menopause, whereas breast and endometrial cancer are caused by unopposed oestrogen action, the new tissue-selective oestrogens and anti-oestrogens, or selective oestrogen-receptor modulators (SERMs), had to recruit new networks to activate or suppress target tissues selectively. New medicines now promise to provide chemoprevention strategies for women at risk for the development of many diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Molecular networks potentially influence the expression of SERM action in a target tissue.
Figure 2: The metabolism of tamoxifen in humans.

Similar content being viewed by others

References

  1. Jordan, V. C. Tamoxifen: a most unlikely pioneering medicine. Nature Rev. Drug Discovery 2, 205–213 (2003).

    Article  CAS  Google Scholar 

  2. Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371–1388 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Gail, M. H. et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J. Natl Cancer Inst. 81, 1879–1886 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Gail, M. H. et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J. Natl Cancer Inst. 91, 1829–1846 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Jordan, V. C. Chemosuppression of breast cancer with tamoxifen: laboratory evidence and future clinical investigations. Cancer Invest. 6, 589–595 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Lerner, L. J. & Jordan, V. C. The development of antiestrogens for the treatment of breast cancer: Eighth Cain Memorial Award Lecture. Cancer Res. 50, 4177–4189 (1990).

    CAS  PubMed  Google Scholar 

  7. Cummings, S. R. et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281, 2189–2197 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Vogel, V. G. et al. The Study of Tamoxifen and Raloxifene (STAR): Report of the National Surgical Adjuvant Breast and Bowel Project P-2 Trial. JAMA 295, 2727–2741 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Jordan, V. C. Selective estrogen receptor modulation: a personal perspective. Cancer Res. 61, 5683–5687 (2001).

    CAS  PubMed  Google Scholar 

  10. Jordan, V. C. & Robinson, S. P. Species-specific pharmacology of antiestrogens: role of metabolism. Fed. Proc. 46, 1870–1874 (1987).

    CAS  PubMed  Google Scholar 

  11. Black, L. J., Jones, C. D. & Falcone, J. F. Antagonism of estrogen action with a new benzothiophene derived antiestrogen. Life Sci. 32, 1031–1036 (1983).

    Article  CAS  PubMed  Google Scholar 

  12. Jordan, V. C., Phelps, E. & Lindgren, J. U. Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res. Treat. 10, 31–35 (1987).

    Article  CAS  PubMed  Google Scholar 

  13. Gottardis, M. M. & Jordan, V. C. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea- induced rat mammary carcinoma model. Cancer Res. 47, 4020–4024 (1987).

    CAS  PubMed  Google Scholar 

  14. Gottardis, M. M., Robinson, S. P., Satyaswaroop, P. G. & Jordan, V. C. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res. 48, 812–815 (1988).

    CAS  PubMed  Google Scholar 

  15. Gottardis, M. M., Ricchio, M. E., Satyaswaroop, P. G. & Jordan, V. C. Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res. 50, 3189–3192 (1990).

    CAS  PubMed  Google Scholar 

  16. Fisher, B. et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl Cancer Inst. 97, 1652–1662 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005).

  18. Melnikow, J. et al. Chemoprevention: drug pricing and mortality: the case of tamoxifen. Cancer 107, 950–958 (2006).

    Article  PubMed  Google Scholar 

  19. Ettinger, B. et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282, 637–645 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Jensen, E. V. & Jordan, V. C. The estrogen receptor: a model for molecular medicine. The Dorothy P. Landon AACR Prize for Translational Research. Clin. Cancer Res. 9, 1980–1989 (2003).

    CAS  PubMed  Google Scholar 

  21. Martino, S. et al. For the CORE investigators. Continuing Outcomes Relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J. Natl Cancer Inst. 96, 1751–1761 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Walsh, B. W. et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 279, 1445–1451 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Barrett-Connor, E. et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N. Engl J. Med. 355, 125–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Jensen, E. V. & Jacobson, H. I. Basic guides to the mechanism of estrogen action. Recent Progr. Hormone Res. 18, 387–414 (1962).

    CAS  Google Scholar 

  25. Greene, G. L. et al. Sequence and expression of human estrogen receptor complementary DNA. Science 231, 1150–1154 (1986).

    Article  CAS  PubMed  Google Scholar 

  26. Kuiper, G. G., Enmark, E., Pelto-Huikko, M., Nilsson, S. & Gustafsson, J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl Acad. Sci. USA 93, 5925–5930 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kuiper, G. G. et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863–870 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Roger, P. et al. Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. Cancer Res. 61, 2537–2541 (2001).

    CAS  PubMed  Google Scholar 

  29. Shaaban, A. M. et al. Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Am. J. Surg. Pathol. 27, 1502–1512 (2003).

    Article  PubMed  Google Scholar 

  30. Paruthiyil, S. et al. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 64, 423–428 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Acconcia, F. et al. Survival versus apoptotic 17beta-estradiol effect: role of ER alpha and ER beta activated non-genomic signaling. J. Cell Physiol. 203, 193–201 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. McInerney, E. M., Weis, K. E., Sun, J., Mosselman, S. & Katzenellenbogen, B. S. Transcription activation by the human estrogen receptor subtype beta (ER beta) studied with ER beta and ER alpha receptor chimeras. Endocrinology 139, 4513–4522 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Barkhem, T. et al. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol. Pharmacol. 54, 105–112 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Hall, J. M. & McDonnell, D. P. The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 140, 5566–5578 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Paech, K. et al. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277, 1508–1510 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Onate, S. A., Tsai, S. Y., Tsai, M. J. & O'Malley, B. W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270, 1354–1357 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Smith, C. L. & O'Malley, B. W. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocrine Rev. 25, 45–71 (2004).

    Article  CAS  Google Scholar 

  38. Jordan, V. C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents. J. Med. Chem. 46, 1081–1111 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Kraichely, D. M., Sun, J., Katzenellenbogen, J. A. & Katzenellenbogen, B. S. Conformational changes and coactivator recruitment by novel ligands for estrogen receptor-alpha and estrogen receptor-beta: correlations with biological character and distinct differences among SRC coactivator family members. Endocrinology 141, 3534–3545 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Shiau, A. K. et al. The structural basis of estrogen receptor/co-activator recognition and the antagonism of this interaction by tamoxifen. Cell 95, 927–937 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Brzozowski, A. M. et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389, 753–758 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Wijayaratne, A. L. et al. Comparative analyses of mechanistic differences among antiestrogens. Endocrinology 140, 5828–5840 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Lonard, D. M. & O'Malley, B. W. The expanding cosmos of nuclear receptor coactivators. Cell 125, 411–414 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Sun, Y. E3 Ubiquitin Ligases as Cancer Targets and Biomarkers. Neoplasia 8, 645–654 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shang, Y., Hu, X., DiRenzo, J., Lazar, M. A. & Brown, M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103, 843–852 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Jordan, V. C., Dix, C. J., Rowsby, L. & Prestwich, G. Studies on the mechanism of action of the nonsteroidal antioestrogen tamoxifen (I. C. I. 46, 474) in the rat. Mol. Cell. Endocrinol. 7, 177–192 (1977).

    Article  CAS  PubMed  Google Scholar 

  47. Horwitz, K. B. & McGuire, W. L. Nuclear mechanisms of estrogen action. Effects of estradiol and anti- estrogens on estrogen receptors and nuclear receptor processing. J. Biol. Chem. 253, 8185–8191 (1978).

    Article  CAS  PubMed  Google Scholar 

  48. Wijayaratne, A. L. & McDonnell, D. P. The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J. Biol. Chem. 276, 35684–35692 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Wu, R. C., Smith, C. L. & O'Malley, B. W. Transcriptional regulation by steroid receptor coactivator phosphorylation. Endocrine Rev. 26, 393–399 (2006).

    Article  CAS  Google Scholar 

  50. Osborne, C. K. et al. Role of the estrogen receptor coactivator AIB1 (SRC3) and HER2/neu in tamoxifen resistance in breast cancer. J. Natl Cancer Inst. 95, 353–361 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Shou, J. et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2–positive breast cancer. J. Natl Cancer Inst. 96, 926–935 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Jordan, V. C., Collins, M. M., Rowsby, L. & Prestwich, G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J. Endocrinol. 75, 305–316 (1977).

    Article  CAS  PubMed  Google Scholar 

  53. Allen, K. E., Clark, E. R. & Jordan, V. C. Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships. Br. J. Pharmacol. 71, 83–91 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jordan, V. C. & Allen, K. E. Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur. J. Cancer 16, 239–251 (1980).

    Article  CAS  PubMed  Google Scholar 

  55. Jordan, V. C. et al. Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient during therapy for advanced breast cancer. Cancer Res. 43, 1446–1450 (1983).

    CAS  PubMed  Google Scholar 

  56. Johnson, M. D. et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res. Treat. 85, 151–159 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Lim, Y. C., Desta, Z., Flockhart, D. A. & Skaar, T. C. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother. Pharmacol. 55, 471–478 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Lim, Y. C. et al. Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J. Pharmacol. Exp. Ther. 318, 503–512 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Stearns, V. et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J. Natl Cancer Inst. 95, 1758–1764 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Jin, Y. et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J. Natl Cancer Inst. 97, 30–39 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Borges, S. et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin. Pharmacol. Ther. 80, 61–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Goetz, M. P. et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J. Clin. Oncol. 23, 9312–9318 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Jordan, V. C. & Gosden, B. Inhibition of the uterotropic activity of estrogens and antiestrogens by the short acting antiestrogen LY117018. Endocrinology 113, 463–468 (1983).

    Article  CAS  PubMed  Google Scholar 

  64. Snyder, K. R., Sparano, N. & Malinowski, J. M. Raloxifene hydrochloride. Am. J. Health Syst. Pharm. 57, 1669–1675 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Kemp, D. C., Fan, P. W. & Stevens, J. C. Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. Drug Metab. Dispos. 30, 694–700 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Jeong, E. J., Lin, H. & Hu, M. Disposition mechanisms of raloxifene in the human intestinal Caco-2 model. J. Pharmacol. Exp. Ther. 310, 376–385 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Falany, J. L., Pilloff, D. E., Leyh, T. S. & Falany, C. N. Sulfation of raloxifene and 4-hydroxytamoxifen by human cytosolic sulfotransferases. Drug Metab. Dispos. 34, 361–368 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Suh, N. et al. Arzoxifene, a new selective estrogen receptor modulator for chemoprevention of experimental breast cancer. Cancer Res. 61, 8412–8415 (2001).

    CAS  PubMed  Google Scholar 

  69. Baselga, J. et al. Randomized, double-blind multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients. Annal. Oncol. 14, 1383–1390 (2003).

    Article  CAS  Google Scholar 

  70. Buzdar, A. et al. Phase II, randomized double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer. J. Clin. Oncol. 21, 1007–1014 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 359, 2134–3139 (2002).

  72. Goss, P. E. et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N. Engl J. Med. 349, 1–10 (2003).

    Article  CAS  Google Scholar 

  73. Howell, A. et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365, 60–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Coombes, R. C. et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N. Engl J. Med. 350, 1081–1092 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Thurlimann, B. et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N. Engl J. Med. 353, 2747–2757 (2005).

    Article  PubMed  Google Scholar 

  76. Goss, P. E. Breast cancer prevention--clinical trials strategies involving aromatase inhibitors. J. Steroid Biochem. Mol. Biol. 86, 487–493 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Goss, P. E. & Strasser-Weippl, K. Prevention strategies with aromatase inhibitors. Clin. Cancer Res. 10, 372S–379S (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Licata, A. A. Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann. Pharmacother. 39, 668–677 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Simpson, E. R. et al. Tissue-specific promoters regulate aromatase cytochrome P450 expression. J. Steroid Biochem. Mol. Biol. 44, 321–330 (1993).

    Article  CAS  PubMed  Google Scholar 

  80. Simpson, E., Clyne, C, Rubin, G. et al. Aromatase-a brief overview. Annu. Rev. Physiol. 64, 93–127 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Safi, R. et al. Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. Cancer Res. 65, 11762–11770 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Diaz-Cruz, E. S., Shapiro, C. L. & Brueggemeier, R. W. Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells. J. Clin. Endocrinol. Metab. 90, 2563–2570 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Su, B., Diaz-Cr, E. S., Landini, S. & Brueggemeier, R. W. Novel sulfonanilide analogues suppress aromatase expression and activity in breast cancer cells independent of COX-2 inhibition. J. Med. Chem. 49, 1413–1419 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Fornander, T. et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1, 117–120 (1989).

    Article  CAS  PubMed  Google Scholar 

  85. Black, L. J., Jones, C. D. & Falcone, J. F. Antagonism of estrogen action with a new benzothiophene derived antiestrogen. Life Sci. 32, 1031–1036 (1983).

    Article  CAS  PubMed  Google Scholar 

  86. Powles, T. J. et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br. J. Cancer 60, 126–131 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Love, R. R. et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N. Engl. J. Med. 326, 852–856 (1992).

    Article  CAS  PubMed  Google Scholar 

  88. Cuzick, J. et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 360, 817–824 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Fisher, B. et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J. Natl Cancer Inst. 86, 527–537 (1994).

    Article  CAS  PubMed  Google Scholar 

  90. Rebbeck, T. R. et al. Estrogen sulfation genes, hormone replacement therapy, and endometrial cancer risk. J. Natl Cancer Inst. 98, 1311–1320 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Horwitz, R. I., Feinstein, A. R., Horwitz, S. M. & Robboy, S. J. Necropsy diagnosis of endometrial cancer and detection-bias in case/control studies. Lancet 2, 66–68 (1981).

    Article  CAS  PubMed  Google Scholar 

  92. Wu, H. et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438, 981–987 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Phillips, D. H., Hewer, A., Grover, P. L., Poon, G. K. & Carmichael, P. L. Tamoxifen does not form detectable DNA adducts in white blood cells of breast cancer patients. Carcinogenesis 17, 1149–1152 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Phillips, D. H. Understanding the genotoxicity of tamoxifen? Carcinogenesis 22, 839–849 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Cavalieri, E. et al. Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim. Biophys. Acta 1766, 63–78 (2006).

    CAS  PubMed  Google Scholar 

  96. Russo, J. et al. 17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells. Faseb J. 20, 1622–1634 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Miller, C. P. et al. Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J. Med. Chem. 44, 1654–1657 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Greenberger, L. M. et al. A new antiestrogen, 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in dol-5-ol hydrochloride (ERA-923), inhibits the growth of tamoxifen-sensitive and-resistant tumors and is devoid of uterotropic effects in mice and rats. Clin. Cancer Res. 7, 3166–3177 (2001).

    CAS  PubMed  Google Scholar 

  99. Rosati, R. L. et al. Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J. Med. Chem. 41, 2928–2931 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Cohen, L. A. et al. Lasofoxifene, a novel selective estrogen receptor modulator with chemopreventive and therapeutic activity in the N-nitroso-N-methylurea-induced rat mammary tumor model. Cancer Res. 61, 8683–8688 (2001).

    CAS  PubMed  Google Scholar 

  101. O'Malley, B. W. Little molecules with big goals. Science 313, 1749–1750 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

V.C.J. is supported by the Department of Defense Breast Program (views and opinions of, and endorsements by the author do not reflect those of the US Army or the Department of Defense), SPORE in Breast Cancer, Fox Chase Cancer Center (FCCC) Core Grant, the Avon Foundation and the Weg Fund, and the Alfred G. Knudson Chair in Cancer Research of the FCCC.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jordan, V. Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer 7, 46–53 (2007). https://doi.org/10.1038/nrc2048

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2048

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing