Breast Cancer Research and Treatment

, Volume 36, Issue 3, pp 267–285 | Cite as

“Studies on the estrogen receptor in breast cancer” — 20 years as a target for the treatment and prevention of cancer

  • V. Craig Jordan
Third Annual William L. McGuire Memorial Lecture


In 1973, McGuire and Chamness (In: O'Malley BW and Means AR (eds) Receptors for Reproductive Hormones, Plenum Press) summarized their work on the estrogen receptor in animal and human breast tumors, and in so doing described a target for therapeutic intervention. At that time there were no clinically useful antiestrogens, but the subsequent development of tamoxifen for breast cancer therapy has revolutionized the approach to treatment. Long-term adjuvant tamoxifen adjuvant therapy (i.e. greater than one year) has proven efficacy to enhance the survival of breast cancer patients. In addition, because there is an associated 40% decrease in contralateral breast cancer during adjuvant tamoxifen therapy and tamoxifen maintains bone density and reduces fatal myocardial infarction, clinical trials to test the worth of tamoxifen as a preventive for breast cancer in high risk women have started in the United States, United Kingdom, and Italy. Initial concerns that long-term tamoxifen causes endometrial cancer have been placed in perspective and analyzed by a review of the literature. Tamoxifen only doubles the normal risk of detecting endometrial cancer, (i.e. to 2 per 1,000 tamoxifen-treated women per year), and 80% of these cases are early stage, good prognosis disease. Annual gynecological examinations and education are essential to provide reassurance for patients.

The success of tamoxifen has encouraged the development of new antiestrogens to exploit the estrogen receptor as a therapeutic target. Droloxifene and TAT-59 mimic the metabolite 4-hydroxytamoxifen in having a high affinity for the estrogen receptor (Jordan et al, J Endocrinol 75:305, 1977). These drugs appear to have a pharmacological profile similar to tamoxifen. In contrast, the new pure antiestrogens have a distinct mechanism of action and will be valuable either as a first line therapy for advanced breast cancer or as a second line endocrine therapy after the failure of long-term adjuvant tamoxifen therapy.

Finally, a new strategy is being developed to exploit the target site specific action of antiestrogens. Raloxifene, an antiestrogen with high affinity for the estrogen receptor but only weak estrogenicity for the uterus, prevents rat mammary tumorigenesis and maintains bone density. The drug is to be evaluated as a treatment for osteoporosis, but may also prevent the development of breast and endometrial cancer in a broad group of treated subjects.

The identification of the estrogen receptor as a target for therapeutic opportunities has proved to be extremely beneficial for the control of breast cancer and has the added potential to control osteoporosis and coronary heart disease in women.

Key words

estrogen receptor tamoxifen prevention endometrial cancer raloxifene long-term adjuvant therapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    McGuire WL, Chamness GC: Studies on the estrogen receptor in breast cancer. In: O'Malley BW, Means AR (eds) Receptors for Reproductive Hormones. Advances in Experimental Medicine and Biology, Plenum Press, New York, 1973, Vol. 37, pp 113–136.Google Scholar
  2. 2.
    Jensen EV, Jacobson HI: Basic guides to the mechanism of estrogen actions. Recent Prog Horm Res 18:387–414, 1962.Google Scholar
  3. 3.
    Gorski J: A hindsight view of early studies on the estrogen receptor: a personal history. Steroids 59:240–243, 1994.Google Scholar
  4. 4.
    McGuire WL, Carbone PP, Vollmer EP (eds): Estrogen Receptors in Human Breast Cancer. Raven Press, New York, 1975.Google Scholar
  5. 5.
    Horwitz KB, McGuire WL, Pearson OH, Segaloff A: Predicting response to endocrine therapy in human breast cancer: a hypothesis. Science 189:726–727, 1975.Google Scholar
  6. 6.
    Horwitz KB, Costlow ME, McGuire WL: MCF-7: A human breast cancer cell line with estrogen, androgen, progesterone and glucocorticoid receptor. Steroids 26:785–795, 1975.Google Scholar
  7. 7.
    Horwitz KB, McGuire WL: Estrogen control of progesterone receptor in human breast cancer. Correlation with nuclear processing of estrogen receptor. J Biol Chem 253:2223–2228, 1978.Google Scholar
  8. 8.
    Horwitz KB, Koseki Y, McGuire WL: Estrogen control of progesterone receptor in human breast cancer: role of estradiol and antiestrogen. Endocrinology 103:1742–1751, 1978.Google Scholar
  9. 9.
    Osborne CK, Yochmowitz MG, Knight WA, McGuire WL: The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer Res 46:2884–2888, 1980.Google Scholar
  10. 10.
    LeMaistre CJ, McGuire WL: Progesterone receptor determinations: a refinement of predictive tests for hormone dependency of breast cancer.In: Jordan VC (ed) Estrogen/Antiestrogen Action and Breast Cancer Therapy. University of Wisconsin Press, Madison, 1986, pp 341–354.Google Scholar
  11. 11.
    Knight WA III, Livingston RB, Gregory EJ, McGuire WL: Estrogen receptor is an independent prognostic factor for early recurrence in breast cancer. Cancer Res 37:4669–4671, 1977.Google Scholar
  12. 12.
    Clark GM, McGuire WL, Hubay CA, Pearson OH, Marshall JS: Progesterone receptors as a prognostic factor in Stage II breast cancer. N Engl J Med 309:1343–1347, 1983.Google Scholar
  13. 13.
    Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O'Malley BW, McGuire WL: Variant human breast tumor estrogen receptor with constitutive transcriptional activity. Cancer Res 51:105–109, 1991.Google Scholar
  14. 14.
    Fuqua SAW, Fitzgerald SD, Allred DC, Elledge RM, Nawaz Z, McDonnell DP, O'Malley BW, Greene GL, McGuire WL: Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors. Cancer Res 52:482–486, 1992.Google Scholar
  15. 15.
    Jordan VC: The development of tamoxifen for breast cancer therapy.In: Jordan VC (ed) Long-Term Tamoxifen Treatment for Breast Cancer. University of Wisconsin Press, Madison, 1994, pp 3–26.Google Scholar
  16. 16.
    Lerner LJ, Holthaus JF, Thompson CR: A nonsteroid estrogen antagonist 1-(p-2-diethylaminoethoxyphenyl)-1-phenyl-2-p-methoxyphenyl-ethanol. Endocrinology 63:295–318, 1958.Google Scholar
  17. 17.
    Lerner LJ: The first nonsteroidal antioestrogen — MER25.In: Sutherland RL, Jordan VC (eds) Nonsteroidal Antioestrogens: Molecular Pharmacology and Antitumour Activity. Academic Press, Sydney, 1981, pp 1–16.Google Scholar
  18. 18.
    Holtkamp DE, Greslin SC, Root CA, Lerner LJ: Gonadotropin inhibiting and antifecundity effects of clomiphene. Proc Soc Exp Biol Med 105:197–201, 1960.Google Scholar
  19. 19.
    Huppert LC: Induction of ovulation with clomiphene citrate. Fert Steril 31:1–8, 1979.Google Scholar
  20. 20.
    Harper MJK, Walpole AL: A new derivative of triphenylethylene: effect on implantation in rats. J Reprod Fertil 13:101–119, 1967.Google Scholar
  21. 21.
    Harper MJK, Walpole AL: Mode of action of ICI 46,474 in preventing implantation in rats. J Endocrinol 37:83–92, 1967.Google Scholar
  22. 22.
    Labsetwar AP: Role of estrogen in ovulation. A study using the estrogen antagonist ICI 46,474. Endocrinology 87:542–551, 1970.Google Scholar
  23. 23.
    Klopper A, Hall M: New synthetic agent for the induction of ovulation: preliminary trials in women. Br Med J i:152–154, 1971.Google Scholar
  24. 24.
    El-Sheika Z, Klopper A, Beck JS: Treatment of menometrorrhagia with an antioestrogen. Clin Endocrinol 1:275–282, 1972.Google Scholar
  25. 25.
    Williamson JG, Ellis JP: The induction of ovulation by tamoxifen. J Obstet Gynaecol Br Commonwealth 80:844–847, 1973.Google Scholar
  26. 26.
    Shaaban MM: Suppression of lactation by an antioestrogen tamoxifen. Eur J Obstet Gynaecol Reprod Biol 415:167–169, 1975.Google Scholar
  27. 27.
    Cole M, Jones CT, Todd IDH: A new antioestrogenic agent in late breast cancer. An early clinical appraisal of ICI 46,474. Br J Cancer 25:270–275, 1971.Google Scholar
  28. 28.
    Ward HWC: Antioestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J i:13–14, 1973.Google Scholar
  29. 29.
    Skidmore J, Walpole AL, Woodburn J: Effect of some triphenylethylenes on oestradiol bindingin vitro to macromolecules from uterus and anterior pituitary. J Endocrinol 52:289–298, 1972.Google Scholar
  30. 30.
    Jordan VC, Koerner S: Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer 11:205–206, 1975.Google Scholar
  31. 31.
    Jordan VC: Antitumour activity of the antioestrogen ICI 46,474 (tamoxifen) in the dimethylbenzanthracene (DMBA)-induced rat mammary carcinoma model. J Steroid Biochem 5:354, 1974.Google Scholar
  32. 32.
    Jordan VC: The antitumour effect of tamoxifen in the dimethylbenzanthracene-induced mammary carcinoma model. Proc Symp Horm Control Breast Cancer. ICI Pharmaceuticals Ltd, Alderley Park, Macclesfield, 1975, pp 11–17.Google Scholar
  33. 33.
    Nicholson RI, Golder MP: The effect of synthetic antioestrogens on the growth and biochemistry of rat mammary tumours. Eur J Cancer 11:571–579, 1975.Google Scholar
  34. 34.
    Jordan VC: Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12:419–424, 1976.Google Scholar
  35. 35.
    Jordan VC, Dowse LJ: Tamoxifen as an antitumour agent: effect on oestrogen binding. J Endocrinol 68:297–303, 1976.Google Scholar
  36. 36.
    Jordan VC, Koerner S: Tamoxifen as an antitumour agent: role of oestradiol and prolactin. J Endocrinol 68:305–310, 1976.Google Scholar
  37. 37.
    Jordan VC, Jaspan T: Tamoxifen as an antitumour agent: oestrogen binding as a predictive test for tumour response. J Endocrinol 68:453–460, 1976.Google Scholar
  38. 38.
    Jordan VC: Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy. Rev Endocr Rel Cancer (October supplement) pp 49–55, 1978.Google Scholar
  39. 39.
    Jordan VC, Dix CJ, Allen KE: The effectiveness of long term treatment in a laboratory model for adjuvant hormone therapy of breast cancer.In: Salmon SE, Jones SE (eds) Adjuvant Therapy of Cancer, Vol. 2. Grune and Stratton, New York, 1979, pp 19–26.Google Scholar
  40. 40.
    Jordan VC, Allen KE: Evaluation of the antitumour activity of the antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16:231–251, 1980.Google Scholar
  41. 41.
    Jordan VC, Allen KE, Dix CJ: Pharmacology of tamoxifen in laboratory animals. Cancer Treat Rep 64:745–759, 1980.Google Scholar
  42. 42.
    Jordan VC: Laboratory studies to develop general principles for the adjuvant treatment of breast cancer with antiestrogens: problems and potential for future clinical applications. Breast Cancer Res Treat 3 (Supplement) S73-S86, 1983.Google Scholar
  43. 43.
    Ludwig Breast Cancer Study Group: Randomized trial of chemoendocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast carcinoma and axillary node metastases. Lanceti:1256–1260, 1985.Google Scholar
  44. 44.
    Ribeiro G, Swindell R: The Christie Hospital tamoxifen (Nolvadex) adjuvant trial for operable breast carcinoma — seven year results. Eur J Cancer Clin Oncol 21:897–900, 1985.Google Scholar
  45. 45.
    Rose C, Thorpe SM, Anderson KW, Pederson BV, Mouridsen HT, Blichert-Toft M, Rasmussen BB: Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lanceti:16–19, 1985.Google Scholar
  46. 46.
    Nolvadex Adjuvant Trial Organization (NATO): Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Lanceti:836–840, 1985.Google Scholar
  47. 47.
    Delozier T, Julien JP, Juret P, Veynet C, Conette JE, Graic Y, Olliver JM, deRancieri E: Adjuvant tamoxifen in postmenopausal breast cancer: preliminary results of a randomized trial. Breast Cancer Res Treat 7:105–119, 1986.Google Scholar
  48. 48.
    Breast Cancer Trials Committee, Scottish Cancer Trials Office: Adjuvant tamoxifen in the management of operable breast cancer: the Scottish trial. Lancetii:171–175, 1987.Google Scholar
  49. 49.
    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 339:71–85, 1992.Google Scholar
  50. 50.
    Fisher B, and National Surgical Adjuvant Breast and Bowel Project investigators: Prolonging tamoxifen therapy for primary breast cancer. Ann Int Med 106:649–654, 1987.Google Scholar
  51. 51.
    Fisher B, Costantino J, Redmond C, and 50 other members of the NSABP: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor positive tumors. N Engl J Med 320:479–484, 1989.Google Scholar
  52. 52.
    Tormey DC, Jordan VC: Long-term tamoxifen adjuvant therapy in node-positive breast cancer: a metabolic and pilot clinical study. Breast Cancer Res Treat 4:297–302, 1984.Google Scholar
  53. 53.
    Falkson HC, Gray R, Wolberg WA, Gilchrist KW, Harris JE, Tormey DC, Falkson G: Adjuvant trials of 12 cycles of CMFPT followed by observation or continuous tamoxifen versus four cycles of CMFPT in postmenopausal women with breast cancer. An Eastern Cooperative Oncology Group Phase III Study. J Clin Oncol 8:599–607, 1990.Google Scholar
  54. 54.
    Tormey DC, Gray R, Abeloff MD, Roseman L, Gilchrist KW, Barylak EJ, Stott P, Falkson G: Adjuvant therapy with doxorubicin regimen and long term tamoxifen in premenopausal breast cancer patients. An Eastern Cooperative Oncology Group Trial. J Clin Oncol 10:1848–1856, 1992.Google Scholar
  55. 55.
    Jordan VC, Phelps E, Lindgren JU: Effect of antiestrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 10:31–35, 1987.Google Scholar
  56. 56.
    Turner RT, Wakley GK, Hannon KS, Bell NH: Tamoxifen inhibits osteoclast mediated resorption of trabecular bone in ovarian hormone-deficient rats. Endocrinology 122:1146–1150, 1988.Google Scholar
  57. 57.
    Love RR, Mazess RB, Tormey DC, Barden HS, Newcomb PA, Jordan VC: Bone mineral density in women with breast cancer treated with adjuvant tamoxifen for at least two years. Breast Cancer Res Treat 12:297–302, 1988.Google Scholar
  58. 58.
    Fornander T, Rutqvist LE, Sjoberg HE, Blomqvist L, Mattson A, Glas U: Long term adjuvant tamoxifen in early breast cancer: effect on bone mineral density in postmenopausal women. J Clin Oncol 8:1019–1024, 1990.Google Scholar
  59. 59.
    Turken S, Siris E, Seldin D, Floster E, Hyman G, Lindsay R: Effect of tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst 81:1086–1088, 1989.Google Scholar
  60. 60.
    Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP, DeMets DL: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852–856, 1992.Google Scholar
  61. 61.
    Ward RL, Morgan G, Dalley D, Kelley PJ: Tamoxifen reduces bone turnover and prevents lumbar spine and proximal femoral bone loss in early postmenopausal women. Bone Min 22:87–94, 1993.Google Scholar
  62. 62.
    Kristensen B, Ejlertsen B, Dalgaard P, Larsen L, Holmegaard SN, Transbol I, Mouridsen HT: Tamoxifen and bone metabolism in postmenopausal, low risk breast cancer patients: a randomized study. J Clin Oncol 12:992–997, 1994.Google Scholar
  63. 63.
    Jordan VC (ed): Long-term Tamoxifen Treatment for Breast Cancer. University of Wisconsin Press, Madison, 1994.Google Scholar
  64. 64.
    Rossner S, Wallgren A: Serum lipoproteins and proteins after breast cancer surgery and effects of tamoxifen. Atherosclerosis 52:339–346, 1984.Google Scholar
  65. 65.
    Bruning PF, Bonfrer JMG, Hart AAM: Tamoxifen, serum lipoproteins and cardiovascular risk. Br J Cancer 58:497–499, 1988.Google Scholar
  66. 66.
    Bertelli G, Pronzato P, Ameroso D: Adjuvant tamoxifen in primary breast cancer: influence on plasma lipids and antithrombin III. Breast Cancer Res Treat 12:307–310, 1988.Google Scholar
  67. 67.
    Bagdade JD, Wolter J, Subbaiah PV: Effects of tamoxifen treatment on plasma lipids and lipoprotein lipid composition. J Clin Endocrinol Metab 70:1132–1135, 1990.Google Scholar
  68. 68.
    Love RR, Weibe DA, Newcomb PA, Cameron L, Leventhal H, Jordan VC, Feyzi J, DeMets DC: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Int Med 115:860–864, 1991.Google Scholar
  69. 69.
    Ingram D: Tamoxifen use, oestrogen binding, and serum lipids in postmenopausal women with breast cancer. Aust NZ J Surg 60:673–675, 1990.Google Scholar
  70. 70.
    Cuzick J, Allen D, Baum M, Barrett J, Clark G, Kakkar V, Melissari E, Moniz C, Moore J, Parsons V, Pemberton K, Pitt P, Richmond W, Houghton J, Riley D: Long-term effects of tamoxifen. Eur J Cancer 29A:15–21, 1992.Google Scholar
  71. 71.
    Dnistrian AM, Schwartz MK, Greenberg EJ: Effect of tamoxifen on serum cholesterol and lipoproteins during chemohormonal therapy. Clin Chim Acta 223:43–52, 1993.Google Scholar
  72. 72.
    Thangaraju M, Kumar K, Gandhirajan R, Sachdanadan P: Effect of tamoxifen on plasma lipids and lipoproteins in postmenopausal women with breast cancer. Cancer 73:659–663, 1994.Google Scholar
  73. 73.
    Love RR: Multisystem biological and symptomatic toxicity of tamoxifen in postmenopausal women.In: Jordan VC (ed) Long-Term Tamoxifen Treatment for Breast Cancer. University of Wisconsin Press, Madison, 1994, pp 57–81.Google Scholar
  74. 74.
    McDonald CC, Stewart HJ: Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. Br Med J 303:435–437, 1991.Google Scholar
  75. 75.
    Jordan VC, Lababidi MK, Langan-Fahey S: Suppression of mouse mammary tumorigenesis by long-term tamoxifen therapy. J Natl Cancer Inst 83:492–496, 1991.Google Scholar
  76. 76.
    Jordan VC: Tamoxifen for breast cancer prevention. Proc Soc Exp Biol Med 208:144–149, 1995.Google Scholar
  77. 77.
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright, Goldgar D, Wiseman R, Kamb A, Skolnick MH: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71, 1994.Google Scholar
  78. 78.
    Bishop DJ: BRCA1, BRCA2, BRCA3... a myriad of breast cancer genes. Eur J Cancer 30A:1738–1739, 1994.Google Scholar
  79. 79.
    Powles TJ, Hardy JR, Ashley SE, Farrington GM, Cosgrove D, Davey JB, Dowsett M, McKinna JA, Nash AG, Sinnett HD, Tillyer CR, Treleaven JG: A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 60:126–133, 1989.Google Scholar
  80. 80.
    Powles TJ, Tillyer CP, Jones AL, Ashley SE, Treleaven J, Davey JB, McKinna JA: Prevention of breast cancer with tamoxifen — an update on the Royal Marsden pilot program. Eur J Cancer 26:680–684, 1990.Google Scholar
  81. 81.
    Powles TJ, Jones AL, Ashley SE, O'Brien MER, Tidy VA, Treleaven J, Cosgrove D, Nash AG, Sacks N, Baum M, McKinna JA, Davey JB: The Royal Marsden Hospital pilot tamoxifen chemoprevention trial. Breast Cancer Res Treat 31:73–82, 1994.Google Scholar
  82. 82.
    Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SF, Cosgrove DO, Campbell S: Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomized breast cancer prevention trial. Lancet 343:1318–1321, 1994.Google Scholar
  83. 83.
    Powles TJ, Ashley S: Endometrial cancer during tamoxifen treatment. Lancet 343:978, 1994.Google Scholar
  84. 84.
    Gail MH, Binton LA, Byar DP, Carle DK, Green SB: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81:1879–1886, 1989.Google Scholar
  85. 85.
    Vanchieri C: Breast cancer study initiated in Italy. J Natl Cancer Inst 84:1555–1556, 1992.Google Scholar
  86. 86.
    Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC: Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 48:812–815, 1988.Google Scholar
  87. 87.
    Assikis VJ, Jordan VC: Gynecological effects of tamoxifen and the association with endometrial carcinoma. Int J Gynecol Obstet (in press).Google Scholar
  88. 88.
    Magriples U, Naftolin F, Schwartz PE, Carcangiu JL: High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 11:485–490, 1993.Google Scholar
  89. 89.
    Fornander T, Rutqvist LE, Cedermark BV, Glas U, Mattsson A, Silfverswärd C, Skoog L, Somell A, Theve T, Wilking N, Askergren J, Hjalmar ML: Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lanceti:117–120, 1989.Google Scholar
  90. 90.
    Fornander T, Hellstrom AC, Moberger B: Descriptive clinicopathologic study of 17 patients with endometrial cancer during or after adjuvant tamoxifen in early breast cancer. J Natl Cancer Inst 85:1850–1855, 1993.Google Scholar
  91. 91.
    Jordan VC, Morrow M: Should clinicians be concerned about the carcinogenic potential of tamoxifen? Eur J Cancer 30A:1714–1721, 1994.Google Scholar
  92. 92.
    Jordan VC, Assikis VJ: Endometrial carcinoma and tamoxifen: clearing up a controversy. Clin Cancer Res (in press).Google Scholar
  93. 93.
    Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM, and other NSABP contributors: Endometrial cancer in tamoxifen treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSAB P) B-14. J Natl Cancer Inst 80:527–537, 1994.Google Scholar
  94. 94.
    Barakat RR, Wong G, Curtin JP, Vlamio V, Hoskins WJ: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histological features. Gynecol Oncol 55:164–168, 1994.Google Scholar
  95. 95.
    Dallenbach-Hellweg G, Hahn U: Mucinous and clear cell adenocarcinomas of the endometrium in patients receiving antiestrogens (tamoxifen) and gestagens. Int J Gynecol Pathol 14:7–15, 1994.Google Scholar
  96. 96.
    Jordan VC, Collins MM, Rowsby L, Prestwich G: A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75:305–316, 1977.Google Scholar
  97. 97.
    Jordan VC, Dix CJ, Naylor KE, Prestwich G, Rowsby L: Non-steroidal antiestrogens: their biological effects and potential mechanisms of action. J Toxicol Environ Health 4:364–390, 1978.Google Scholar
  98. 98.
    Malet C, Gompel A, Spritzer P, Bicout N, Yaneva H, Mowzowicz I, Kutten N, Mauvais-Jarvis P: Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal human breast cells in culture. Cancer Res 48:7193–7199, 1988.Google Scholar
  99. 99.
    Toko T, Sugimoto Y, Matsuo KI, Yamasaki R, Takeda S, Wiereba K, Asao T, Yamada Y: TAT-59, a new triphenylethylene derivative with antitumor activity against hormone dependent tumors. Eur J Cancer 26:397–404, 1990.Google Scholar
  100. 100.
    Hasmann M, Rattel B, Loser R: Preclinical data for droloxifene. Cancer Lett 84:101–116, 1994.Google Scholar
  101. 101.
    Rauschning W, Pritchard KI: Droloxifene, a new antiestrogen: its role in metastatic breast cancer. Breast Cancer Res Treat 31:83–94, 1994.Google Scholar
  102. 102.
    Jordan VC, Fenuik L, Allen KE, Cotton RC, Richardson DN, Walpole AL, Bowler J: Structural derivatives of tamoxifen and oestradiol 3 methyl ether as potential alkylating antiestrogens. Eur J Cancer Clin Oncol 17:193–200, 1981.Google Scholar
  103. 103.
    Bucourt R, Vignau M, Torelli V, Richard-Foy H, Geynet C, Secco-Millet C, Redeuilh G, Bailieu EE: New biospecific adsorbents for the purification of estradiol receptor. J Biol Chem 253:8221–8228, 1978.Google Scholar
  104. 104.
    Wakeling AE, Bowler J: Steroidal pure antiestrogens. J Endocrinol 112:R7-R10, 1987.Google Scholar
  105. 105.
    Bowler J, Lilley TJ, Pittman JD, Wakeling AE: Novel steroidal pure antiestrogens. Steroids 54:71–99, 1989.Google Scholar
  106. 106.
    Wakeling AE, Dukes M, Bowler J: A potent specific pure antiestrogen with clinical potential. Cancer Res 51:3867–3873, 1991.Google Scholar
  107. 107.
    Osborne CK, Coronado EB, Robinson JP: Human breast cancer in athymic nude mice: cytostatic effects of long-term antiestrogenic activity. Eur J Cancer Clin Oncol 232:1189–1196, 1987.Google Scholar
  108. 108.
    Gottardis MM, Jordan VC: Development of tamoxifen stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48:5183–5187, 1988.Google Scholar
  109. 109.
    Gottardis MM, Wagner RJ, Borden EC, Jordan VC: Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growthin vivo andin vitro. Cancer Res 49:4765–4769, 1989.Google Scholar
  110. 110.
    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 49:4090–4093, 1989.Google Scholar
  111. 111.
    Osborne CK, Jarman M, McCague R, Coronado EB, Hilsenbeck SG, Wakeling AE: The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth. Cancer Chemother Pharmacol 34:89–95, 1994.Google Scholar
  112. 112.
    Jordan VC: A therapeutic withdrawal can make a strategic advance. Ann Oncol 3:587–588, 1992.Google Scholar
  113. 113.
    DeFriend DJ, Howell A, Nicholson RI, Andersen E, Dowsett M, Marbel RE, Blamey RW, Bundred NJ, Robertson JF, Saunders C, Baum M, Walton P, Sutcliffe F, Wakeling AE: Investigation of a pure new antiestrogen (ICI 182,780) in women with primary breast cancer. Cancer Res 54:408–414, 1994.Google Scholar
  114. 114.
    Nicholson RI, Francis AB, McClelland RA, Manning DL, Gee JMW: Pure anti-oestrogens (ICI 164,384 and ICI 182,780) and breast cancer: is the attainment of complete estrogen withdrawal worthwhile? Rev Endocr Rel Cancer 1:5–17, 1994.Google Scholar
  115. 115.
    Dukes M, Miller D, Wakeling AE, Waterton JC: Antiuterotrophic effect of a pure antioestrogen, ICI 182,780: magnetic resonance imaging of the uterus in ovariectomized monkeys. J Endocrinol 135:239–247, 1992.Google Scholar
  116. 116.
    Dukes M, Waterton JC, Wakeling AE: Antiuterotrophic effect of pure antioestrogen ICI 182,780 in adult female monkeys (Macaca nemestrina): quantitative magnetic resonance imaging. J Endocrinol 138:203–210, 1993.Google Scholar
  117. 117.
    Lerner LJ, Jordan VC: Development of antiestrogens and their use in breast cancer: Eighth Cain Memorial Award Lecture. Cancer Res 50:4177–4189, 1990.Google Scholar
  118. 118.
    Morrow M, Jordan VC: Risk factors and the prevention of breast cancer with tamoxifen.In: Fentiman IS, Taylor-Papadimitriou J (eds) Breast Cancer. Cancer Surveys, Vol. 18, Cold Spring Harbor Laboratory Press, 1993, pp 211–230.Google Scholar
  119. 119.
    Black LJ, Jones CD, Falcone JF: Antagonism of estrogen action with a new benzothiopene-derived antiestrogen. Life Sci 32:1031–1036 1983.Google Scholar
  120. 120.
    Gottardis MM, Jordan VC: The antitumor action of keoxifene and tamoxifen in the N-nitrosomethylureainduced rat mammary carcinoma model. Cancer Res 47:4020–4024, 1981.Google Scholar
  121. 121.
    Black LJ, Sato M, Towley ER, Magee DE, Bekele A, Williams DC, Cullinan GJ, Bendele R, Kaufman RF, Bersch WR, Frolik, CA, Termine JD, Bryant HD: Raloxifene (LY139481HC1) prevents bone loss and reduces serum cholesterol without causing uterine hypotrophy in ovariectomized rats. J Clin Invest 93:63–69, 1994.Google Scholar
  122. 122.
    Jordan VC: What if ICI 46,474 (tamoxifen) had been found to produce rat liver tumors in 1973? Ann Oncol 6:29–34, 1995.Google Scholar
  123. 123.
    Tellez C, Jordan VC: Hormonal treatment for advanced breast cancer.In: Bland K (ed) Surg Oncol Clin N America (in press).Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • V. Craig Jordan
    • 1
  1. 1.Robert H. Lurie Cancer CenterNorthwestern University Medical SchoolChicagoUSA

Personalised recommendations