Advertisement

The SERM Saga, Something from Nothing: American Cancer Society/SSO Basic Science Lecture

  • V. Craig JordanEmail author
Breast Oncology

Abstract

Background

The discovery of nonsteroidal antiestrogens created a new group of medicines looking for an application; however, at the time, cytotoxic chemotherapy was the modality of choice to treat all cancers. Antiestrogens were orphan drugs until 1971, with the passing of the National Cancer Act. This enabled laboratory innovations to aid patient care.

Methods

This article traces the strategic application of tamoxifen to treat breast cancer by targeting the estrogen receptor (ER), deploying long-term adjuvant tamoxifen therapy, and becoming the first chemopreventive for any cancer. Laboratory discoveries from the University of Wisconsin Comprehensive Cancer Center (UWCCC) are described that address a broad range of biological issues with tamoxifen. These translated to improvements in clinical care.

Results

Tamoxifen was studied extensively at UWCCC in the 1980s for the development of acquired resistance to long-term therapy. Additionally, the long-term metabolism of tamoxifen and regulation of growth factors were also studied. A concern with tamoxifen use for chemoprevention was that an antiestrogen would increase bone loss and atherosclerosis. Laboratory studies with tamoxifen and keoxifene (subsequently named raloxifene) demonstrated that ‘nonsteroidal antiestrogens’ maintained bone density, and this translated into successful clinical trials with tamoxifen at UWCCC. However, tamoxifen also increased endometrial cancer growth; this discovery in the laboratory translated into changes in clinical care. Selective estrogen receptor modulators (SERMs) were born at UWCCC.

Conclusions

There are now five US FDA-approved SERMs, all with discovery origins at UWCCC. Women’s health was revolutionized as SERMs have the ability to treat multiple diseases by switching target sites around a woman’s body on or off.

Notes

Acknowledgment

This article is dedicated to members of the University of Wisconsin Tamoxifen Team. The question can be asked ‘What was achieved for the team members during 1980–1995’? My Ph.D. student Anna C. Riegel (née Tate) and I arrived in 1980 to build a research program that did not exist. During the 15-year period, the tamoxifen team never exceeded two dozen students and staff. In 1983, I inherited the Directorship of the steroid receptor laboratory for Southern Wisconsin, including its six staff. This was a daunting prospect so I called my mentor, the late Dr. Bill McGuire, in San Antonio to express my uncertainty at the challenge ahead. He explained that I was looking at this incorrectly. ‘This was an opportunity’ and I should treat it as such. He was absolutely correct. During the whole of this period, I had stable funding from National Institutes of Health (NIH) grants and pharmaceutical contracts, as well as philanthropic donations to the laboratory. I was promoted to Professor of Human Oncology and Pharmacology in 1985 and appointed Director of the Breast Cancer Research and Treatment Program at the University of Wisconsin Comprehensive Cancer Center in 1987. Ten Ph.D. students successfully received their degrees and publications flowed: refereed research papers (146), invited refereed reviews (22), editorials (11), book chapters (91), books edited (2), and international meetings organized (2). Members of the Wisconsin Tamoxifen Team are show in Figs. 3, 4 and 5. I would like to thank the benefactors of the Dallas/Fort Worth Living Legend Chair of Cancer Research, George and Barbara Bush Endowment for Cancer Research, and the Cancer Center Support Grant P30-CA16672 (Peter Pisters).

Disclosures

V. Craig Jordan has no conflicts of interest to declare.

References

  1. 1.
    Jordan VC. Tamoxifen as the first targeted long-term adjuvant therapy for breast cancer. Endocr Relat Cancer. 2014;21:R235–46.Google Scholar
  2. 2.
    Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971;25:270–5.Google Scholar
  3. 3.
    Jordan VC, Koerner S. Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer. 1975;11:205–6.Google Scholar
  4. 4.
    Jordan VC, Allen KE. Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer. 1980;16:239–51.Google Scholar
  5. 5.
    Jordan VC, Allen KE, Dix CJ. Pharmacology of tamoxifen in laboratory animals. Cancer Treat Rep. 1980;64:745–59.Google Scholar
  6. 6.
    Jordan VC. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer. 1976;12:419–24.Google Scholar
  7. 7.
    Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451–67.Google Scholar
  8. 8.
    Gorski J, Toft D, Shyamala G, Smith D, Notides A. Hormone receptors: studies on the interaction of estrogen with the uterus. Recent Prog Horm Res. 1968;24;45–80.Google Scholar
  9. 9.
    Knabbe C, Lippman ME, Wakefield LM, Flanders KC, Kasid A, Derynck R, et al. Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell. 1987;48:417–28.Google Scholar
  10. 10.
    Robinson SP, Jordan VC. Antiestrogenic action of toremifene on hormone-dependent, -independent, and heterogeneous breast tumor growth in the athymic mouse. Cancer Res. 1989;49:1758–62.Google Scholar
  11. 11.
    Cormier ME, Jordan VC. Contrasting ability of antiestrogens to inhibit MCF-7 growth stimulated by estradiol or epidermal growth factor. Eur J Cancer Clin Oncol. 1989;25:57–63.Google Scholar
  12. 12.
    Cormier EM, Wolf MF, Jordan VC. Decrease in estradiol-stimulated progesterone receptor production in MCF-7 cells by epidermal growth factor and possible clinical implication for paracrine-regulated breast cancer growth. Cancer Res. 1989;49:576–80.Google Scholar
  13. 13.
    Robinson SP, Jordan VC. The paracrine stimulation of MCF-7 cells by MDA-MB-231 cells: possible role in antiestrogen failure. Eur J Cancer Clin Oncol. 1989;25:493–7.Google Scholar
  14. 14.
    Catherino WH, Jeng MH, Jordan VC. Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism. Br J Cancer. 1993;67:945–52.Google Scholar
  15. 15.
    Jeng MH, Jordan VC. Growth stimulation and differential regulation of transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, and TGF beta 3 messenger RNA levels by norethindrone in MCF-7 human breast cancer cells. Mol Endocrinol. 1991;5:1120–8.Google Scholar
  16. 16.
    Jeng MH, Langan-Fahey SM, Jordan VC. Estrogenic actions of RU486 in hormone-responsive MCF-7 human breast cancer cells. Endocrinology. 1993;132:2622–30.Google Scholar
  17. 17.
    Jeng MH, Parker CJ, Jordan VC. Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation. Cancer Res. 1992;52:6539–46.Google Scholar
  18. 18.
    Gottardis MM, Jordan VC. Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res. 1988;48:5183–7.Google Scholar
  19. 19.
    Gottardis MM, Wagner RJ, Borden EC, Jordan VC. Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro. Cancer Res. 1989;49:4765–9.Google Scholar
  20. 20.
    Gottardis MM, Jiang SY, Jeng MH, Jordan VC. Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res. 1989;49:4090–3.Google Scholar
  21. 21.
    Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002;20:3386–95.Google Scholar
  22. 22.
    Wolf DM, Jordan VC. A laboratory model to explain the survival advantage observed in patients taking adjuvant tamoxifen therapy. Recent Results Cancer Res. 1993;127:23–33.Google Scholar
  23. 23.
    Yao K, Lee ES, Bentrem DJ, England G, Schafer JI, O’Regan RM, et al. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res. 2000;6:2028–36.Google Scholar
  24. 24.
    Jordan VC. The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer. 2015;22:R1–31.Google Scholar
  25. 25.
    Abderrahman B, Jordan VC. The modulation of estrogen-induced apoptosis as an interpretation of the women’s health initiative trials. Expert Rev Endocrinol Metab. 2016;11:81–6.Google Scholar
  26. 26.
    Jordan VC. Linking estrogen-induced apoptosis with decreases in mortality following long-term adjuvant tamoxifen therapy. J Natl Cancer Inst. 2014;106: pii: dju296.Google Scholar
  27. 27.
    Murphy CS, Meisner LF, Wu SQ, Jordan VC. Short- and long-term estrogen deprivation of T47D human breast cancer cells in culture. Eur J Cancer Clin Oncol. 1989;25:1777–88.Google Scholar
  28. 28.
    Welshons WV, Jordan VC. Adaptation of estrogen-dependent MCF-7 cells to low estrogen (phenol red-free) culture. Eur J Cancer Clin Oncol. 1987;23:1935–9.Google Scholar
  29. 29.
    Pink JJ, Jordan VC. Models of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines. Cancer Res. 1996;56:2321–30.Google Scholar
  30. 30.
    Murphy CS, Pink JJ, Jordan VC. Characterization of a receptor-negative, hormone-nonresponsive clone derived from a T47D human breast cancer cell line kept under estrogen-free conditions. Cancer Res. 1990;50:7285–92.Google Scholar
  31. 31.
    Pink JJ, Bilimoria MM, Assikis J, Jordan VC. Irreversible loss of the oestrogen receptor in T47D breast cancer cells following prolonged oestrogen deprivation. Br J Cancer. 1996;74:1227–36.Google Scholar
  32. 32.
    Jiang SY, Wolf DM, Yingling JM, Chang C, Jordan VC. An estrogen receptor positive MCF-7 clone that is resistant to antiestrogens and estradiol. Mol Cell Endocrinol. 1992;90:77–86.Google Scholar
  33. 33.
    Lewis JS, Osipo C, Meeke K, Jordan VC. Estrogen-induced apoptosis in a breast cancer model resistant to long-term estrogen withdrawal. J Steroid Biochem Mol Biol. 2005;94:131–41.Google Scholar
  34. 34.
    Ariazi EA, Cunliffe HE, Lewis-Wambi JS, Slifker MJ, Willis AL, Ramos P, et al. Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time. Proc Natl Acad Sci USA. 2011;108:18879–86.Google Scholar
  35. 35.
    Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, et al. Lower-dose versus high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA. 2009;302:774–80.Google Scholar
  36. 36.
    Allen KE, Clark ER, Jordan VC. Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships. Br J Pharmacol. 1980;71:83–91.Google Scholar
  37. 37.
    Jordan VC, Collins MM, Rowsby L, Prestwich G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977;75:305–16.Google Scholar
  38. 38.
    Jordan VC. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 1: receptor interactions. J Med Chem. 2003;46:883–908.Google Scholar
  39. 39.
    Jordan VC. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2: clinical considerations and new agents. J Med Chem. 2003;46:1081–1111.Google Scholar
  40. 40.
    Jordan VC, Bowser-Finn RA. Binding of [3H]monohydroxytamoxifen by immature rat tissues in vivo. Endocrinology. 1982;110:1281–91.Google Scholar
  41. 41.
    Tate AC, DeSombre ER, Greene GL, Jensen EV, Jordan VC. Interaction of [3H] estradiol—and [3H] monohydroxytamoxifen-estrogen receptor complexes with a monoclonal antibody. Breast Cancer Res Treat. 1983;3:267–77.Google Scholar
  42. 42.
    Tate AC, Greene GL, DeSombre ER, Jensen EV, Jordan VC. Differences between estrogen- and antiestrogen-estrogen receptor complexes from human breast tumors identified with an antibody raised against the estrogen receptor. Cancer Res. 1984;44:1012–8.Google Scholar
  43. 43.
    Tate AC, Jordan VC. Nuclear [3H]4-hydroxytamoxifen (4-OHTAM)- and [3H]estradiol (E2)-estrogen receptor complexes in the MCF-7 breast cancer and GH3 pituitary tumor cell lines. Mol Cell Endocrinol. 1984;36:211–9.Google Scholar
  44. 44.
    Tate AC, Lieberman ME, Jordan VC. The inhibition of prolactin synthesis in GH3 rat pituitary tumor cells by monohydroxytamoxifen is associated with changes in the properties of the estrogen receptor. J Steroid Biochem. 1984;20:391–5.Google Scholar
  45. 45.
    Lieberman ME, Maurer RA, Gorski J. Estrogen control of prolactin synthesis in vitro. Proc Natl Acad Sci USA. 1978;75:5946–9.Google Scholar
  46. 46.
    Jordan VC, Koch R, Langan S, McCague R. Ligand interaction at the estrogen receptor to program antiestrogen action: a study with nonsteroidal compounds in vitro. Endocrinology. 1988;122:1449–54.Google Scholar
  47. 47.
    Jordan VC, Koch R, Mittal S, Schneider MR. Oestrogenic and antioestrogenic actions in a series of triphenylbut-1-enes: modulation of prolactin synthesis in vitro. Br J Pharmacol. 1986;87:217–23.Google Scholar
  48. 48.
    Jordan VC, Lieberman ME. Estrogen-stimulated prolactin synthesis in vitro. Classification of agonist, partial agonist, and antagonist actions based on structure. Mol Pharmacol. 1984;26:279–85.Google Scholar
  49. 49.
    Jordan VC, Lieberman ME, Cormier E, Koch R, Bagley JR, Ruenitz PC. Structural requirements for the pharmacological activity of nonsteroidal antiestrogens in vitro. Mol Pharmacol. 1984;26:272–8.Google Scholar
  50. 50.
    Lieberman ME, Jordan VC, Fritsch M, Santos MA, Gorski J. Direct and reversible inhibition of estradiol-stimulated prolactin synthesis by antiestrogens in vitro. J Biol Chem. 1983;258:4734–40.Google Scholar
  51. 51.
    Murphy CS, Jordan VC. Structural components necessary for the antiestrogenic activity of tamoxifen. J Steroid Biochem. 1989;34:407–11.Google Scholar
  52. 52.
    Murphy CS, Langan-Fahey SM, McCague R, Jordan VC. Structure-function relationships of hydroxylated metabolites of tamoxifen that control the proliferation of estrogen-responsive T47D breast cancer cells in vitro. Mol Pharmacol. 1990;38:737–43.Google Scholar
  53. 53.
    Murphy CS, Parker CJ, McCague R, Jordan VC. Structure-activity relationships of nonisomerizable derivatives of tamoxifen: importance of hydroxyl group and side chain positioning for biological activity. Mol Pharmacol. 1991;39:421–8.Google Scholar
  54. 54.
    Jordan VC. Laboratory models of breast cancer to aid the elucidation of antiestrogen action. J Lab Clin Med. 1987;109:267–77.Google Scholar
  55. 55.
    Lieberman ME, Gorski J, Jordan VC. An estrogen receptor model to describe the regulation of prolactin synthesis by antiestrogens in vitro. J Biol Chem. 1983;258:4741–5.Google Scholar
  56. 56.
    Wolf DM, Jordan VC. Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice. Breast Cancer Res Treat. 1994;31:117–27.Google Scholar
  57. 57.
    Wolf DM, Jordan VC. The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain. Breast Cancer Res Treat. 1994;31:129–38.Google Scholar
  58. 58.
    Catherino WH, Wolf DM, Jordan VC. A naturally occurring estrogen receptor mutation results in increased estrogenicity of a tamoxifen analog. Mol Endocrinol. 1995;9:1053–63.Google Scholar
  59. 59.
    Jiang SY, Jordan VC. Growth regulation of estrogen receptor-negative breast cancer cells transfected with complementary DNAs for estrogen receptor. J Natl Cancer Inst. 1992;84:580–91.Google Scholar
  60. 60.
    Levenson AS, Catherino WH, Jordan VC. Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptor. J Steroid Biochem Mol Biol. 1997;60:261–8.Google Scholar
  61. 61.
    Levenson AS, Jordan VC. The key to the antiestrogenic mechanism of raloxifene is amino acid 351 (aspartate) in the estrogen receptor. Cancer Res. 1998;58:1872–5.Google Scholar
  62. 62.
    Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997;389:753–8.Google Scholar
  63. 63.
    Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998;95:927–37.Google Scholar
  64. 64.
    Fanning SW, Mayne CG, Dharmarajan V, Carlson KE, Martin TA, Novick SJ, et al. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. Elife. 2016;5:pii:e12792.Google Scholar
  65. 65.
    Brown RR, Bain R, Jordan VC. Determination of tamoxifen and metabolites in human serum by high-performance liquid chromatography with post-column fluorescence activation. J Chromatogr. 1983;272:351–8.Google Scholar
  66. 66.
    Jordan VC, Bain RR, Brown RR, Gosden B, Santos MA. Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient sera during therapy for advanced breast cancer. Cancer Res. 1983;43:1446–50.Google Scholar
  67. 67.
    Jordan VC, Fritz NF, Langan-Fahey S, Thompson M, Tormey DC. Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent. J Natl Cancer Inst. 1991;83:1488–91.Google Scholar
  68. 68.
    Ravdin PM, Fritz NF, Tormey DC, Jordan VC. Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen. Cancer Res. 1988;48:1026–9.Google Scholar
  69. 69.
    Tormey DC, Jordan VC. Long-term tamoxifen adjuvant therapy in node-positive breast cancer: a metabolic and pilot clinical study. Breast Cancer Res Treat. 1984;4:297–302.Google Scholar
  70. 70.
    Langan-Fahey SM, Tormey DC, Jordan VC. Tamoxifen metabolites in patients on long-term adjuvant therapy for breast cancer. Eur J Cancer. 1990;26:883–8.Google Scholar
  71. 71.
    Bain RR, Jordan VC. Identification of a new metabolite of tamoxifen in patient serum during breast cancer therapy. Biochem Pharmacol. 1983;32:373–5.Google Scholar
  72. 72.
    Archer DF, Goldstein SR, Simon JA, Waldbaum AS, Sussman SA, Altomare C, et al. Efficacy and safety of ospemifene in postmenopausal women with moderate-to-severe vaginal dryness: a phase 3, randomized, double-blind, placebo-controlled, multicenter trial. Menopause. Epub 28 Jan 2019.  https://doi.org/10.1097/gme.0000000000001292.
  73. 73.
    Wolf DM, Langan-Fahey SM, Parker CJ, McCague R, Jordan VC. Investigation of the mechanism of tamoxifen-stimulated breast tumor growth with nonisomerizable analogues of tamoxifen and metabolites. J Natl Cancer Inst. 1993;85:806–12.Google Scholar
  74. 74.
    Robinson SP, Langan-Fahey SM, Johnson DA, Jordan VC. Metabolites, pharmacodynamics, and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient. Drug Metab Dispos. 1991;19:36–43.Google Scholar
  75. 75.
    Robinson SP, Langan-Fahey SM, Jordan VC. Implications of tamoxifen metabolism in the athymic mouse for the study of antitumor effects upon human breast cancer xenografts. Eur J Cancer Clin Oncol. 1989;25:1769–76.Google Scholar
  76. 76.
    Jordan VC, Robinson SP. Species-specific pharmacology of antiestrogens: role of metabolism. Fed Proc. 1987;46:1870–4.Google Scholar
  77. 77.
    Jordan VC, Phelps E, Lindgren JU. Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat. 1987;10:31–5.Google Scholar
  78. 78.
    Gottardis MM, Jordan VC. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res. 1987;47:4020–4.Google Scholar
  79. 79.
    Turner RT, Wakley GK, Hannon KS, Bell NH. Tamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats. J Bone Miner Res. 1987;2:449–56.Google Scholar
  80. 80.
    Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, et al. Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest. 1994;93:63–9.Google Scholar
  81. 81.
    Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res. 1988;48:812–5.Google Scholar
  82. 82.
    Jordan VC. Tamoxifen and endometrial cancer. Lancet. 1988;2:1019.Google Scholar
  83. 83.
    Jordan VC. Tamoxifen and endometrial cancer. Lancet. 1989;1:733–4.Google Scholar
  84. 84.
    Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfverswärd C, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet. 1989;1:117–20.Google Scholar
  85. 85.
    Lerner LJ, Jordan VC. Development of antiestrogens and their use in breast cancer: eighth Cain memorial award lecture. Cancer Res. 1990;50:4177–89.Google Scholar
  86. 86.
    Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med. 1992;326:852–6.Google Scholar
  87. 87.
    Love RR, Newcomb PA, Wiebe DA, Surawicz TS, Jordan VC, Carbone PP, et al. Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer. J Natl Cancer Inst. 1990;82:1327–32.Google Scholar
  88. 88.
    RR Love, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med. 1991;115:860–4.Google Scholar
  89. 89.
    Jordan VC, Morrow M. Should clinicians be concerned about the carcinogenic potential of tamoxifen? Eur J Cancer. 1994;30A:1714–21.Google Scholar
  90. 90.
    Dragan VP, Vaughan J, Jordan VC, Pitot HC. Comparison of the effects of tamoxifen and toremifene on liver and kidney tumor promotion in female rats. Carcinogenesis. 1995;16:2733–41.Google Scholar
  91. 91.
    Dragan YP, Fahey S, Nuwaysir E, Sattler C, Babcock K, Vaughan J, et al. The effect of tamoxifen and two of its non-isomerizable fixed-ring analogs on multistage rat hepatocarcinogenesis. Carcinogenesis. 1996;17:585–94.Google Scholar
  92. 92.
    Dragan YP, Fahey S, Street K, Vaughan J, Jordan VC, Pitot HC. Studies of tamoxifen as a promoter of hepatocarcinogenesis in female Fischer F344 rats. Breast Cancer Res Treat. 1994;31:11–25.Google Scholar
  93. 93.
    Nuwaysir EF, Dragan YP, Jefcoate CR, Jordan VC, Pitot HC. Effects of tamoxifen administration on the expression of xenobiotic metabolizing enzymes in rat liver. Cancer Res. 1995;55:1780–6.Google Scholar
  94. 94.
    Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, 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. 1999;281:2189–97.Google Scholar
  95. 95.
    Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. Effects of tamoxifen versus raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727–41.Google Scholar
  96. 96.
    Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila). 2010;3:696–706.Google Scholar
  97. 97.
    Robinson SP, Mauel DA, Jordan VC. Antitumor actions of toremifene in the 7,12-dimethylbenzanthracene (DMBA)-induced rat mammary tumor model. Eur J Cancer Clin Oncol. 1988;24:1817–21.Google Scholar
  98. 98.
    Robinson SP, Parker CJ, Jordan VC. Preclinical studies with toremifene as an antitumor agent. Breast Cancer Res Treat. 1990;16 Suppl:S9–17.Google Scholar
  99. 99.
    Robinson SP, Koch R, Jordan VC. 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. 1988;48:784–7.Google Scholar
  100. 100.
    Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med. 2010;362:686–96.Google Scholar

Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  1. 1.Dallas/Fort Worth Living Legend Chair of Cancer ResearchDepartment of Breast Medical Oncology, University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations