Skip to main content
SpringerLink
Log in

A Novel Strategy to Improve Women’s Health: Selective Estrogen Receptor Modulators

  • Chapter
  • First Online:
Estrogen Receptor and Breast Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Tamoxifen is the first selective estrogen receptor modulator. The extensive clinical and laboratory testing during the 1980s and 1990s raised questions about why there is target site specificity of tamoxifen in different species, i.e., tamoxifen is an estrogen in mice but a complete anti-estrogen in chicks. Additionally, tamoxifen has estrogen-like effects to lower circulating cholesterol, build postmenopausal bone in women, and stimulate the uterus and endometrial cancer growth but paradoxically prevents breast tumor growth. These observations lead to the SERM solution to prevent osteoporosis with a safe SERM but to prevent breast cancer at the same time. Raloxifene is the result with no increase in endometrial cancer incidence. There are now five FDA-approved SERMS available for use: tamoxifen, raloxifene, bazedoxifene, toremifene, and ospemifene. All have connections with discovery and basic research in Jordan’s laboratory.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Furr BJ, Jordan VC (1984) The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25(2):127–205

    Article  CAS  PubMed  Google Scholar 

  2. Terenius L (1971) Structure-activity relationships of anti-oestrogens with regard to interaction with 17-beta-oestradiol in the mouse uterus and vagina. Acta Endocrinol 66(3):431–447

    Article  CAS  Google Scholar 

  3. Harper MJ, Walpole AL (1967) A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil 13(1):101–119

    Article  CAS  PubMed  Google Scholar 

  4. Sutherland R, Mester J, Baulieu EE (1977) Tamoxifen is a potent pure anti-oestrogen in chick oviduct. Nature 267(5610):434–435. https://doi.org/10.1038/267434a0

    Article  CAS  PubMed  Google Scholar 

  5. Fromson JM, Pearson S, Bramah S (1973) The metabolism of tamoxifen (I.C.I. 46,474). I. In laboratory animals. Xenobiotica 3(11):693–709. https://doi.org/10.3109/00498257309151594

    Article  CAS  PubMed  Google Scholar 

  6. Lyman SD, Jordan VC (1985) Metabolism of tamoxifen and its uterotrophic activity. Biochem Pharmacol 34(15):2787–2794

    Article  CAS  PubMed  Google Scholar 

  7. Allen KE, Clark ER, Jordan VC (1980) Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships. Br J Pharmacol 71(1):83–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Robinson SP, Langan-Fahey SM, Jordan VC (1989) Implications of tamoxifen metabolism in the athymic mouse for the study of antitumor effects upon human breast cancer xenografts. Eur J Cancer Clin Oncol 25(12):1769–1776

    Article  CAS  PubMed  Google Scholar 

  9. Sutherland RL, Murphy LC, San Foo M, Green MD, Whybourne AM, Krozowski ZS (1980) High-affinity anti-oestrogen binding site distinct from the oestrogen receptor. Nature 288(5788):273–275

    Article  CAS  PubMed  Google Scholar 

  10. Lyman SD, Jordan VC (1985) Possible mechanisms for the agonist actions of tamoxifen and the antagonist actions of MER-25 (ethamoxytriphetol) in the mouse uterus. Biochem Pharmacol 34(15):2795–2806

    Article  CAS  PubMed  Google Scholar 

  11. Katzenellenbogen BS, Miller MA, Eckert RL, Sudo K (1983) Antiestrogen pharmacology and mechanism of action. J Steroid Biochem 19(1A):59–68

    Article  CAS  PubMed  Google Scholar 

  12. Miller MA, Katzenellenbogen BS (1983) Characterization and quantitation of antiestrogen binding sites in estrogen receptor-positive and -negative human breast cancer cell lines. Cancer Res 43(7):3094–3100

    CAS  PubMed  Google Scholar 

  13. Lieberman ME, Jordan VC, Fritsch M, Santos MA, Gorski J (1983) Direct and reversible inhibition of estradiol-stimulated prolactin synthesis by antiestrogens in vitro. J Biol Chem 258(8):4734–4740

    CAS  PubMed  Google Scholar 

  14. Jordan VC, Lieberman ME, Cormier E, Koch R, Bagley JR, Ruenitz PC (1984) Structural requirements for the pharmacological activity of nonsteroidal antiestrogens in vitro. Mol Pharmacol 26(2):272–278

    CAS  PubMed  Google Scholar 

  15. Jordan VC, Lieberman ME (1984) Estrogen-stimulated prolactin synthesis in vitro. Classification of agonist, partial agonist, and antagonist actions based on structure. Mol Pharmacol 26(2):279–285

    CAS  PubMed  Google Scholar 

  16. Jordan VC, Koch R, Mittal S, Schneider MR (1986) Oestrogenic and antioestrogenic actions in a series of triphenylbut-1-enes: modulation of prolactin synthesis in vitro. Br J Pharmacol 87(1):217–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lieberman ME, Gorski J, Jordan VC (1983) An estrogen receptor model to describe the regulation of prolactin synthesis by antiestrogens in vitro. J Biol Chem 258(8):4741–4745

    CAS  PubMed  Google Scholar 

  18. Pantelouris EM (1968) Absence of thymus in a mouse mutant. Nature 217(5126):370–371

    Article  CAS  PubMed  Google Scholar 

  19. Rygaard J, Povlsen CO (1969) Heterotransplantation of a human malignant tumour to “nude” mice. Acta Pathol Microbiol Scand 77(4):758–760

    Article  CAS  PubMed  Google Scholar 

  20. Soule HD, McGrath CM (1980) Estrogen responsive proliferation of clonal human breast carcinoma cells in athymic mice. Cancer Lett 10(2):177–189

    Article  CAS  PubMed  Google Scholar 

  21. Weinstein Y (1978) Impairment of the hypothalamo-pituitary-ovarian axis of the athymic “nude” mouse. Mech Ageing Dev 8(1):63–68

    Article  CAS  PubMed  Google Scholar 

  22. Shafie SM, Grantham FH (1981) Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 67(1):51–56

    CAS  PubMed  Google Scholar 

  23. Jordan VC, Robinson SP (1987) Species-specific pharmacology of antiestrogens: role of metabolism. Fed Proc 46(5):1870–1874

    CAS  PubMed  Google Scholar 

  24. Satyaswaroop PG, Zaino RJ, Mortel R (1984) Estrogen-like effects of tamoxifen on human endometrial carcinoma transplanted into nude mice. Cancer Res 44(9):4006–4010

    CAS  PubMed  Google Scholar 

  25. Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC (1988) Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 48(4):812–815

    CAS  PubMed  Google Scholar 

  26. Hardell L (1988) Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet 2(8610):563

    Article  CAS  PubMed  Google Scholar 

  27. Jordan VC (1989) Tamoxifen and endometrial cancer. Lancet 1(8640):733–734

    Article  CAS  PubMed  Google Scholar 

  28. Jordan VC (1988) Tamoxifen and endometrial cancer. Lancet 2(8618):1019

    CAS  PubMed  Google Scholar 

  29. Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfversward C, Skoog L, Somell A, Theve T, Wilking N et al (1989) Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1(8630):117–120

    Article  CAS  PubMed  Google Scholar 

  30. Assikis VJ, Jordan VC (1995) A realistic assessment of the association between tamoxifen and endometrial cancer. Endocr Relat Cancer 2(3):235–241. https://doi.org/10.1677/erc.0.0020235

    Article  CAS  Google Scholar 

  31. Jordan VC, Assikis VJ (1995) Endometrial carcinoma and tamoxifen: clearing up a controversy. Clin Cancer Res 1(5):467–472

    CAS  PubMed  Google Scholar 

  32. Jordan VC, Lababidi MK, Mirecki DM (1990) Anti-oestrogenic and anti-tumour properties of prolonged tamoxifen therapy in C3H/OUJ mice. Eur J Cancer 26(6):718–721

    Article  CAS  PubMed  Google Scholar 

  33. Jordan VC, Lababidi MK, Langan-Fahey S (1991) Suppression of mouse mammary tumorigenesis by long-term tamoxifen therapy. J Natl Cancer Inst 83(7):492–496

    Article  CAS  PubMed  Google Scholar 

  34. Jordan VC (1990) Long-term adjuvant tamoxifen therapy for breast cancer. Breast Cancer Res Treat 15(3):125–136

    Article  CAS  PubMed  Google Scholar 

  35. Jordan VC (2007) Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer 7(1):46–53. https://doi.org/10.1038/nrc2048

    Article  CAS  PubMed  Google Scholar 

  36. Yager JD, Davidson NE (2006) Mechanisms of disease: estrogen carcinogenesis in breast cancer. N Engl J Med 354(3):270–282. https://doi.org/10.1056/NEJMra050776

    Article  CAS  PubMed  Google Scholar 

  37. Jordan VC, Phelps E, Lindgren JU (1987) Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 10(1):31–35

    Article  CAS  PubMed  Google Scholar 

  38. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP, DeMets DL (1992) Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326(13):852–856. https://doi.org/10.1056/NEJM199203263261302

    Article  CAS  PubMed  Google Scholar 

  39. Love RR, Wiebe DA, Newcomb PA, Cameron L, Leventhal H, Jordan VC, Feyzi J, DeMets DL (1991) Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115(11):860–864

    Article  CAS  PubMed  Google Scholar 

  40. Lerner LJ, Jordan VC (1990) Development of antiestrogens and their use in breast cancer: eighth Cain memorial award lecture. Cancer Res 50(14):4177–4189

    CAS  PubMed  Google Scholar 

  41. Turner RT, Wakley GK, Hannon KS, Bell NH (1988) Tamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats. Endocrinology 122(3):1146–1150. https://doi.org/10.1210/endo-122-3-1146

    Article  CAS  PubMed  Google Scholar 

  42. Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, Cullinan GJ, Bendele R, Kauffman RF, Bensch WR et al (1994) Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 93(1):63–69. https://doi.org/10.1172/JCI116985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jordan VC, Collins MM, Rowsby L, Prestwich G (1977) A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75(2):305–316

    Article  CAS  PubMed  Google Scholar 

  44. Jordan VC, Allen KE (1980) Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16(2):239–251

    Article  CAS  PubMed  Google Scholar 

  45. Jordan VC (2003) Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents. J Med Chem 46(7):1081–1111. https://doi.org/10.1021/jmj020450x

    Article  CAS  PubMed  Google Scholar 

  46. Deshmane V, Krishnamurthy S, Melemed AS, Peterson P, Buzdar AU (2007) Phase III double-blind trial of arzoxifene compared with tamoxifen for locally advanced or metastatic breast cancer. J Clin Oncol 25(31):4967–4973. https://doi.org/10.1200/JCO.2006.09.5992

    Article  CAS  PubMed  Google Scholar 

  47. Kendler DL, Palacios S, Cox DA, Stock J, Alam J, Dowsett SA, Zanchetta J (2012) Arzoxifene versus raloxifene: effect on bone and safety parameters in postmenopausal women with osteoporosis. Osteoporos Int 23(3):1091–1101. https://doi.org/10.1007/s00198-011-1587-0

    Article  CAS  PubMed  Google Scholar 

  48. Rosati RL, Da Silva Jardine P, Cameron KO, Thompson DD, Ke HZ, Toler SM, Brown TA, Pan LC, Ebbinghaus CF, Reinhold AR, Elliott NC, Newhouse BN, Tjoa CM, Sweetnam PM, Cole MJ, Arriola MW, Gauthier JW, Crawford DT, Nickerson DF, Pirie CM, Qi H, Simmons HA, Tkalcevic GT (1998) Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J Med Chem 41(16):2928–2931. https://doi.org/10.1021/jm980048b

    Article  CAS  PubMed  Google Scholar 

  49. Ke HZ, Paralkar VM, Grasser WA, Crawford DT, Qi H, Simmons HA, Pirie CM, Chidsey-Frink KL, Owen TA, Smock SL, Chen HK, Jee WS, Cameron KO, Rosati RL, Brown TA, Dasilva-Jardine P, Thompson DD (1998) Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models. Endocrinology 139(4):2068–2076. https://doi.org/10.1210/endo.139.4.5902

    Article  CAS  PubMed  Google Scholar 

  50. Ke HZ, Qi H, Crawford DT, Chidsey-Frink KL, Simmons HA, Thompson DD (2000) Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat. Endocrinology 141(4):1338–1344. https://doi.org/10.1210/endo.141.4.7408

    Article  CAS  PubMed  Google Scholar 

  51. Cohen LA, Pittman B, Wang CX, Aliaga C, Yu L, Moyer JD (2001) LAS, 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(24):8683–8688

    CAS  PubMed  Google Scholar 

  52. Prakash C, Johnson KA, Schroeder CM, Potchoiba MJ (2008) Metabolism, distribution, and excretion of a next generation selective estrogen receptor modulator, lasofoxifene, in rats and monkeys. Drug Metab Dispos 36(9):1753–1769. https://doi.org/10.1124/dmd.108.021808

    Article  CAS  PubMed  Google Scholar 

  53. Moffett A, Ettinger M, Bolognese M (2004) Lasofoxifene, a next generation SERM, is effective in preventing loss of BMD and reducing LDL-C in postmenopausal women. J Bone Miner Res 19:S96

    Article  Google Scholar 

  54. Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, Goldstein S, Sriram U, Lee A, Thompson J, Armstrong RA, Thompson DD, Powles T, Zanchetta J, Kendler D, Neven P, Eastell R, Investigators PS (2010) Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 362(8):686–696. https://doi.org/10.1056/NEJMoa0808692

    Article  CAS  PubMed  Google Scholar 

  55. Davidson M, Moffett A, Welty F (2005) Extraskeletal effects of lasofoxifene on postmenopausal women. J Bone Miner Res 20:S173

    Google Scholar 

  56. McClung MR, Siris E, Cummings S, Bolognese M, Ettinger M, Moffett A, Emkey R, Day W, Somayaji V, Lee A (2006) Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene. Menopause 13(3):377–386. https://doi.org/10.1097/01.gme.0000188736.69617.4f

    Article  PubMed  Google Scholar 

  57. Robinson SP, Koch R, Jordan VC (1988) In vitro estrogenic actions in rat and human cells of hydroxylated derivatives of D16726 (zindoxifene), an agent with known antimammary cancer activity in vivo. Cancer Res 48(4):784–787

    CAS  PubMed  Google Scholar 

  58. Miller CP, Collini MD, Tran BD, Harris HA, Kharode YP, Marzolf JT, Moran RA, Henderson RA, Bender RH, Unwalla RJ, Greenberger LM, Yardley JP, Abou-Gharbia MA, Lyttle CR, Komm BS (2001) Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J Med Chem 44(11):1654–1657

    Article  CAS  PubMed  Google Scholar 

  59. Miller PD, Chines AA, Christiansen C, Hoeck HC, Kendler DL, Lewiecki EM, Woodson G, Levine AB, Constantine G, Delmas PD (2008) Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res 23(4):525–535. https://doi.org/10.1359/jbmr.071206

    Article  CAS  PubMed  Google Scholar 

  60. Pinkerton JV, Archer DF, Utian WH, Menegoci JC, Levine AB, Chines AA, Constantine GD (2009) Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis. Menopause 16(6):1102–1108. https://doi.org/10.1097/gme.0b013e3181a816be

    Article  PubMed  Google Scholar 

  61. Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, Constantine GD, Chines AA (2008) Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 23(12):1923–1934. https://doi.org/10.1359/jbmr.080710

    Article  CAS  PubMed  Google Scholar 

  62. Smith DC, Prentice R, Thompson DJ, Herrmann WL (1975) Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293(23):1164–1167. https://doi.org/10.1056/NEJM197512042932302

    Article  CAS  PubMed  Google Scholar 

  63. Ziel HK, Finkle WD (1975) Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293(23):1167–1170. https://doi.org/10.1056/NEJM197512042932303

    Article  CAS  PubMed  Google Scholar 

  64. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A, Investigators WHI (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA 289(24):3243–3253. https://doi.org/10.1001/jama.289.24.3243

    Article  CAS  PubMed  Google Scholar 

  65. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Women's Health Initiative Steering C (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291(14):1701–1712. https://doi.org/10.1001/jama.291.14.1701

    Article  CAS  PubMed  Google Scholar 

  66. Haddow A, Watkinson JM, Paterson E, Koller PC (1944) Influence of synthetic oestrogens upon advanced malignant disease. Br Med J 2:393–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Haddow A (1970) David A. Karnofsky memorial lecture. Thoughts on chemical therapy. Cancer 26(4):737–754

    Article  CAS  PubMed  Google Scholar 

  68. Early Breast Cancer Trialists’ Collaborative G, Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378(9793):771–784. https://doi.org/10.1016/S0140-6736(11)60993-8

    Article  CAS  Google Scholar 

  69. Jordan VC (2014) Linking estrogen-induced apoptosis with decreases in mortality following long-term adjuvant tamoxifen therapy. J Natl Cancer Inst 106(11):dju296. https://doi.org/10.1093/jnci/dju296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yao K, Lee ES, Bentrem DJ, England G, Schafer JI, O'Regan RM, Jordan VC (2000) Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 6(5):2028–2036

    CAS  PubMed  Google Scholar 

  71. Wolf DM, Jordan VC (1993) A laboratory model to explain the survival advantage observed in patients taking adjuvant tamoxifen therapy. Recent Results Cancer Res 127:23–33

    Article  CAS  PubMed  Google Scholar 

  72. Song RX, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, Yue W, Wang J, Santen RJ (2001) Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 93(22):1714–1723

    Article  CAS  PubMed  Google Scholar 

  73. Jordan VC (2015) The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer 22(1):R1–R31. https://doi.org/10.1530/ERC-14-0448

    Article  CAS  PubMed  Google Scholar 

  74. Abderrahman B, Jordan VC (2016) The modulation of estrogen-induced apoptosis as an interpretation of the Women’s Health Initiative trials. Expert Rev Endocrinol Metab 11:81–86. https://doi.org/10.1586/17446651.2016.1128324

    Article  CAS  PubMed  Google Scholar 

  75. MacGregor JI, Jordan VC (1998) Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 50(2):151–196

    CAS  PubMed  Google Scholar 

  76. Kharode Y, Bodine PV, Miller CP, Lyttle CR, Komm BS (2008) The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology 149(12):6084–6091. https://doi.org/10.1210/en.2008-0817

    Article  CAS  PubMed  Google Scholar 

  77. Ariazi EA, Cunliffe HE, Lewis-Wambi JS, Slifker MJ, Willis AL, Ramos P, Tapia C, Kim HR, Yerrum S, Sharma CG, Nicolas E, Balagurunathan Y, Ross EA, Jordan VC (2011) Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time. Proc Natl Acad Sci U S A 108(47):18879–18886. https://doi.org/10.1073/pnas.1115188108

    Article  PubMed  PubMed Central  Google Scholar 

  78. Sweeney EE, Fan P, Jordan VC (2014) Molecular modulation of estrogen-induced apoptosis by synthetic progestins in hormone replacement therapy: an insight into the women's health initiative study. Cancer Res 74(23):7060–7068. https://doi.org/10.1158/0008-5472.CAN-14-1784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Obiorah IE, Fan P, Jordan VC (2014) Breast cancer cell apoptosis with phytoestrogens is dependent on an estrogen-deprived state. Cancer Prev Res 7(9):939–949. https://doi.org/10.1158/1940-6207.Capr-14-0061

    Article  CAS  Google Scholar 

  80. Bain RR, Jordan VC (1983) Identification of a new metabolite of tamoxifen in patient serum during breast cancer therapy. Biochem Pharmacol 32(2):373–375

    Article  CAS  PubMed  Google Scholar 

  81. Jordan VC, Bain RR, Brown RR, Gosden B, Santos MA (1983) Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient sera during therapy for advanced breast cancer. Cancer Res 43(3):1446–1450

    CAS  PubMed  Google Scholar 

  82. Jordan VC (2017) Concerns about methodology of a trial investigating vaginal health during aromatase inhibitor therapy for breast cancer. JAMA Oncol 3(8):1141–1141. https://doi.org/10.1001/jamaoncol.2017.2074

    Article  PubMed  Google Scholar 

  83. Jordan VC (1984) Biochemical pharmacology of antiestrogen action. Pharmacol Rev 36(4):245–276

    CAS  PubMed  Google Scholar 

  84. Jordan VC (2013) Estrogen action, selective estrogen receptor modulators and women’s health: progress and promise. Imperial College Press, London

    Book  Google Scholar 

  85. Murphy CS, Langan-Fahey SM, McCague R, Jordan VC (1990) Structure-function relationships of hydroxylated metabolites of tamoxifen that control the proliferation of estrogen-responsive T47D breast cancer cells in vitro. Mol Pharmacol 38(5):737–743

    CAS  PubMed  Google Scholar 

  86. Murphy CS, Parker CJ, McCague R, Jordan VC (1991) Structure-activity relationships of nonisomerizable derivatives of tamoxifen: importance of hydroxyl group and side chain positioning for biological activity. Mol Pharmacol 39(3):421–428

    CAS  PubMed  Google Scholar 

  87. Jordan VC (1987) Laboratory models of breast cancer to aid the elucidation of antiestrogen action. J Lab Clin Med 109(3):267–277

    CAS  PubMed  Google Scholar 

  88. Wolf DM, Jordan VC (1994) The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain. Breast Cancer Res Treat 31(1):129–138

    Article  CAS  PubMed  Google Scholar 

  89. Jiang SY, Jordan VC (1992) Growth regulation of estrogen receptor-negative breast cancer cells transfected with complementary DNAs for estrogen receptor. J Natl Cancer Inst 84(8):580–591

    Article  CAS  PubMed  Google Scholar 

  90. Catherino WH, Wolf DM, Jordan VC (1995) A naturally occurring estrogen receptor mutation results in increased estrogenicity of a tamoxifen analog. Mol Endocrinol 9(8):1053–1063. https://doi.org/10.1210/mend.9.8.7476979

    Article  CAS  PubMed  Google Scholar 

  91. Levenson AS, Catherino WH, Jordan VC (1997) Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptor. J Steroid Biochem Mol Biol 60(5–6):261–268

    Article  CAS  PubMed  Google Scholar 

  92. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389(6652):753–758. https://doi.org/10.1038/39645

    Article  CAS  PubMed  Google Scholar 

  93. Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95(7):927–937

    Article  CAS  PubMed  Google Scholar 

  94. Levenson AS, Jordan VC (1998) The key to the antiestrogenic mechanism of raloxifene is amino acid 351 (aspartate) in the estrogen receptor. Cancer Res 58(9):1872–1875

    CAS  PubMed  Google Scholar 

  95. MacGregor Schafer J, Liu H, Bentrem DJ, Zapf JW, Jordan VC (2000) Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex is induced by substituting glycine for aspartate at amino acid 351. Cancer Res 60(18):5097–5105

    CAS  PubMed  Google Scholar 

  96. Schafer JI, Liu H, Tonetti DA, Jordan VC (1999) The interaction of raloxifene and the active metabolite of the antiestrogen EM-800 (SC 5705) with the human estrogen receptor. Cancer Res 59(17):4308–4313

    CAS  PubMed  Google Scholar 

  97. Bentrem D, Dardes R, Liu H, MacGregor-Schafer J, Zapf J, Jordan V (2001) Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen. Endocrinology 142(2):838–846. https://doi.org/10.1210/endo.142.2.7932

    Article  CAS  PubMed  Google Scholar 

  98. Liu H, Lee ES, Deb Los Reyes A, Zapf JW, Jordan VC (2001) Silencing and reactivation of the selective estrogen receptor modulator-estrogen receptor alpha complex. Cancer Res 61(9):3632–3639

    CAS  PubMed  Google Scholar 

  99. Liu H, Park WC, Bentrem DJ, McKian KP, Reyes Ade L, Loweth JA, Schafer JM, Zapf JW, Jordan VC (2002) Structure-function relationships of the raloxifene-estrogen receptor-alpha complex for regulating transforming growth factor-alpha expression in breast cancer cells. J Biol Chem 277(11):9189–9198. https://doi.org/10.1074/jbc.M108335200

    Article  CAS  PubMed  Google Scholar 

  100. Jordan VC (2003) Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2(3):205–213. https://doi.org/10.1038/nrd1031

    Article  CAS  PubMed  Google Scholar 

  101. McDonnell DP, Clemm DL, Hermann T, Goldman ME, Pike JW (1995) Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 9(6):659–669. https://doi.org/10.1210/mend.9.6.8592512

    Article  CAS  PubMed  Google Scholar 

  102. Paige LA, Christensen DJ, Gron H, Norris JD, Gottlin EB, Padilla KM, Chang CY, Ballas LM, Hamilton PT, McDonnell DP, Fowlkes DM (1999) Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. Proc Natl Acad Sci U S A 96(7):3999–4004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Norris JD, Fan D, Stallcup MR, McDonnell DP (1998) Enhancement of estrogen receptor transcriptional activity by the coactivator GRIP-1 highlights the role of activation function 2 in determining estrogen receptor pharmacology. J Biol Chem 273(12):6679–6688

    Article  CAS  PubMed  Google Scholar 

  104. Norris JD, Paige LA, Christensen DJ, Chang CY, Huacani MR, Fan D, Hamilton PT, Fowlkes DM, McDonnell DP (1999) Peptide antagonists of the human estrogen receptor. Science 285(5428):744–746

    Article  CAS  PubMed  Google Scholar 

  105. Wijayaratne AL, Nagel SC, Paige LA, Christensen DJ, Norris JD, Fowlkes DM, McDonnell DP (1999) Comparative analyses of mechanistic differences among antiestrogens. Endocrinology 140(12):5828–5840. https://doi.org/10.1210/endo.140.12.7164

    Article  CAS  PubMed  Google Scholar 

  106. Hall JM, McDonnell DP, Korach KS (2002) Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements. Mol Endocrinol 16(3):469–486. https://doi.org/10.1210/mend.16.3.0814

    Article  CAS  PubMed  Google Scholar 

  107. Onate SA, Tsai SY, Tsai MJ, O’Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270(5240):1354–1357

    Article  CAS  PubMed  Google Scholar 

  108. Smith CL, O’Malley BW (2004) Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 25(1):45–71. https://doi.org/10.1210/er.2003-0023

    Article  CAS  PubMed  Google Scholar 

  109. Jordan VC, O’Malley BW (2007) Selective estrogen-receptor modulators and antihormonal resistance in breast cancer. J Clin Oncol 25(36):5815–5824. https://doi.org/10.1200/JCO.2007.11.3886

    Article  CAS  PubMed  Google Scholar 

  110. Fan P, Jordan VC (2013) An emerging principle: selective nuclear receptor modulators. In: Jordan VC (ed) Estrogen action, selective estrogen receptor modulators and women’s health: progress and promise. Imperial College Press, London, pp 431–456

    Chapter  Google Scholar 

  111. Greene GL, Closs LE, Fleming H, DeSombre ER, Jensen EV (1977) Antibodies to estrogen receptor: immunochemical similarity of estrophilin from various mammalian species. Proc Natl Acad Sci U S A 74(9):3681–3685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Greene GL, Fitch FW, Jensen EV (1980) Monoclonal antibodies to estrophilin: probes for the study of estrogen receptors. Proc Natl Acad Sci U S A 77(1):157–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Greene GL, Nolan C, Engler JP, Jensen EV (1980) Monoclonal antibodies to human estrogen receptor. Proc Natl Acad Sci U S A 77(9):5115–5119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J (1986) Sequence and expression of human estrogen receptor complementary DNA. Science 231(4742):1150–1154

    Article  CAS  PubMed  Google Scholar 

  115. Jordan VC, Bowser-Finn RA (1982) Binding of [3H]monohydroxytamoxifen by immature rat tissues in vivo. Endocrinology 110(4):1281–1291. https://doi.org/10.1210/endo-110-4-1281

    Article  CAS  PubMed  Google Scholar 

  116. Tate AC, Greene GL, DeSombre ER, Jensen EV, Jordan VC (1984) Differences between estrogen- and antiestrogen-estrogen receptor complexes from human breast tumors identified with an antibody raised against the estrogen receptor. Cancer Res 44(3):1012–1018

    CAS  PubMed  Google Scholar 

  117. Lieberman ME, Maurer RA, Gorski J (1978) Estrogen control of prolactin synthesis in vitro. Proc Natl Acad Sci U S A 75(12):5946–5949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bouton MM, Raynaud JP (1979) The relevance of interaction kinetics in determining biological response to estrogens. Endocrinology 105(2):509–515. https://doi.org/10.1210/endo-105-2-509

    Article  CAS  PubMed  Google Scholar 

  119. Gottardis MM, Jordan VC (1988) Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48(18):5183–5187

    CAS  PubMed  Google Scholar 

  120. Gottardis MM, Wagner RJ, Borden EC, Jordan VC (1989) Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro. Cancer Res 49(17):4765–4769

    CAS  PubMed  Google Scholar 

  121. Gottardis MM, Jiang SY, Jeng MH, Jordan VC (1989) Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res 49(15):4090–4093

    CAS  PubMed  Google Scholar 

  122. Beall PT, Misra LK, Young RL, Spjut HJ, Evans HJ, LeBlanc A (1984) Clomiphene protects against osteoporosis in the mature ovariectomized rat. Calcif Tissue Int 36(1):123–125

    Article  CAS  PubMed  Google Scholar 

  123. Powles TJ, Hardy JR, Ashley SE, Farrington GM, Cosgrove D, Davey JB, Dowsett M, McKinna JA, Nash AG, Sinnett HD et al (1989) A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 60(1):126–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Love RR, Mazess RB, Tormey DC, Barden HS, Newcomb PA, Jordan VC (1988) Bone mineral density in women with breast cancer treated with adjuvant tamoxifen for at least two years. Breast Cancer Res Treat 12(3):297–302

    Article  CAS  PubMed  Google Scholar 

  125. Lewis JS, Meeke K, Osipo C, Ross EA, Kidawi N, Li TY, Bell E, Chandel NS, Jordan VC (2005) Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation. J Natl Cancer Inst 97(23):1746–1759. https://doi.org/10.1093/jnci/dji400

    Article  CAS  PubMed  Google Scholar 

  126. Gottardis MM, Jordan VC (1987) Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res 47(15):4020–4024

    CAS  PubMed  Google Scholar 

  127. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC (1999) 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(23):2189–2197

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Breast Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Balkees Abderrahman & V. Craig Jordan

Authors
  1. Balkees Abderrahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Craig Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. Craig Jordan .

Editor information

Editors and Affiliations

  1. Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Xiaoting Zhang

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Abderrahman, B., Jordan, V.C. (2019). A Novel Strategy to Improve Women’s Health: Selective Estrogen Receptor Modulators. In: Zhang, X. (eds) Estrogen Receptor and Breast Cancer. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-99350-8_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-99350-8_8

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-99349-2

  • Online ISBN: 978-3-319-99350-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation