Antiestrogens: Mechanism of Action and Effects in Breast Cancer

  • Kathryn B. Horwitz
  • William L. McGuire


Several of the nonsteroidal antiestrogens are in experimental use for the treatment of breast cancer. The treatment goal is to obtain, with minimal toxicity, specific control over cell growth by chemical means, thereby avoiding, on the one hand, pharmacologic doses of hormones and, on the other, major surgical ablative procedures.(1) One rationale for use of estrogen antagonists is an outgrowth of our current awareness of the role of estrogen receptors (ERs) and estrogen in breast cancer. Recent reports show that hormone dependence can be predicted by use of ER measurements. If estrogen antagonists block the action of estrogen at its receptor, it would be possible to obtain, by noninvasive means, the same therapeutic end as ablative hormonal procedures. Despite considerable research to that end, however, our knowledge of the mechanism of antiestrogen action remains unclear. The purpose of this review is to summarize this research. We will review first some of the biological activities of antiestrogens in normal tissues, and the mechanisms that have been proposed for their effects, then the role of antiestrogens in experimental animal breast cancer, and the data currently available on use of antiestrogens in humans and human breast cancer.


Breast Cancer Estrogen Receptor Nuclear Receptor Mammary Tumor Estrogen Action 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    P. P. Carbone, Editorial: Antiestrogens and breast cancer treatment, Ann. Intern. Med. 83(5), 730–731 (1975).PubMedGoogle Scholar
  2. 2.
    G. W. Duncan, S. C. Lyster, J.J. Clark, and D. Lednicer, Antifertility activities of two diphenyl-dihydronaphthalene derivatives, Proc. Soc. Exp. Biol. Med. 112, 439–442 (1963).Google Scholar
  3. 3.
    G. DiPasquale, C. L. Rassaert, E. McDougall, and L. Tripp, Action of an estradiol-17ß antagonist in intact, ovariectomized, hypophysectomized and hypophysectomized-ovariectomized rats, Contraception 5, 39–51 (1972).PubMedGoogle Scholar
  4. 4.
    L. Terenius, Structure-activity relationships of anti-estrogens with regard to interaction with 17ß-oestradiol in the mouse uterus and vagina, Acta Endocrinol. 66, 431–447 (1971).PubMedGoogle Scholar
  5. 5.
    L. Terenius, Hexoestrol analogues as probes of oestrogen receptors. II. Importance of hydrogen-bonding groups for binding to uterine tissue and for uterotrophic activity, Acta Pharmacol. Toxicol. 31, 449–455 (1972).Google Scholar
  6. 6.
    V. C. Jordan, Prolonged antioestrogenic activity of ICI 46,474 in the ovariectomized mouse, J. Reprod. Fertil. 42, 251–258 (1975).PubMedGoogle Scholar
  7. 7.
    K. D. Schulz, and S. August, Female endocrine control mechanisms during the neonatal period, Acta Endocrinol. 74, 144–156 (1973).PubMedGoogle Scholar
  8. 8.
    B. S. Katzenellenbogen, E. R. Ferguson, and N. C. Lan, Fundamental differences in the action of estrogens and antiestrogens on the uterus: Comparison between compounds with similar duration of action, Endocrinology 100, 1252–1259 (1977).PubMedGoogle Scholar
  9. 9.
    E. R. Ferguson and B. S. Katzenellenbogen, A comparative study of antiestrogen action: Temporal patterns of antagonism of estrogen stimulated uterine growth and effects on estrogen receptor levels, Endocrinology 100, 1242–1251 (1977).PubMedGoogle Scholar
  10. 10.
    J. H. Clark, J. N. Anderson, and E. J. Peck Jr., Oestrogen receptors and antagonism of steroid hormone action, Nature (London) 251, 246–248 (1974).Google Scholar
  11. 11.
    C. W. Emmens and L. Martin, Biological activities of U-11100A, J. Reprod. Fertil. 9, 269–275 (1965).Google Scholar
  12. 12.
    L. Terenius and I. Ljungkvist, Aspects on the mode of action of antiestrogens and antiprogestogens, Gynecol Invest. 3, 96–107 (1972).PubMedGoogle Scholar
  13. 13.
    K. D. Schulz, S. August, K. Gosde, and G. Kramer, Studies on the anti-oestrogenlike action of clomiphene citrate in animal experiments, Gynecol. Invest. 3, 135–141 (1972).PubMedGoogle Scholar
  14. 14.
    B. S. Katzenellenbogen and J. A. Katzenellenbogen, Antiestrogens: Studies using an in vitro estrogen-responsive uterine system, Biochem. Biophys. Res. Commun. 50, 1152–1159 (1973).PubMedGoogle Scholar
  15. 15.
    V. C. Jordan, Antiestrogenic and antitumor properties of tamoxifen in laboratory animals, Cancer Treatment Rep. 60, 1409–1419 (1976).Google Scholar
  16. 16.
    J. H. Clark, J. N. Anderson, and E. J. Peck, Jr., Estrogen receptor anti-estrogen complex: A typical binding by uterine nuclei and effects on uterine growths, Steroids 22, 707–718 (1973).PubMedGoogle Scholar
  17. 17.
    I. Ljungkvist and L. Terenius, MER 25 and U11–100A, two antiestrogens with tissue selective and incomplete estrogenic activity, on rat uterus, Contraception 10, 395–404 (1974).PubMedGoogle Scholar
  18. 18.
    J. W. Hardin, J. H. Clark, S. R. Glasser, and E. J. Peck Jr., RNA polymerase activity and uterine growth: Differential stimulation by estradiol, estriol, nafoxidine, Biochemistry 15, 1370–1374 (1976).PubMedGoogle Scholar
  19. 19.
    N. C. Lan and B. S. Katzenellenbogen, Temporal relationships between hormone receptor binding and biological responses in the uterus: Studies with short- and long-acting derivatives of estriol, Endocrinology 98, 220–227 (1976).PubMedGoogle Scholar
  20. 20.
    B. R. Komisaruk and C. Beyer, Differential antagonism, by MER-25, of behavioral and morphological effects of estradiol benzoate in rats, Horm. Behav. 3, 63–70 (1972).PubMedGoogle Scholar
  21. 21.
    B. S. Katzenellenbogen and J. A. Katzenellenbogen, Antiestrogens: Studies using an in vitro estrogen-responsive uterine system, Biochem. Biophys. Res. Commun. 50, 1152–1159 (1973).PubMedGoogle Scholar
  22. 22.
    B. S. Katzenellenbogen and E. R. Ferguson, Antiestrogen action in the uterus: Biological ineffectiveness of nuclear bound estradiol after antiestrogen, Endocrinology 97, 1–12 (1975).PubMedGoogle Scholar
  23. 23.
    F. Capony and H. Rochefort, In vivo effect of anti-estrogen on the localization and replenishment of estrogen receptor, Mol. Cell. Endocrinol. 3, 233–251, 1975.PubMedGoogle Scholar
  24. 24.
    W. H. Bulger and D. Kupfer, Induction of uterine ornithine decarboxylase (ODC) by antiestrogens—Inhibition of estradiol-mediated induction of ODC: A possible mechanism of action of antiestrogens, Endocrinol. Res. Commun. 3, 209–218 (1976).Google Scholar
  25. 25.
    M. K. Harper and A. L. Walpole, A new derivative of triphenylethylene: Effect on implantation and mode of action in rats, J. Reprod. Fertil. 13, 101–119 (1967).PubMedGoogle Scholar
  26. 26.
    M. Geschwendt, The effect on antiestrogens on egg yolk protein synthesis and estrogen-binding to chromatin in the rooster liver, Biochem. Biophys. Acta 399, 395–402 (1975).Google Scholar
  27. 27.
    J. N. Anderson, E.J. Peck Jr., and J. H. Clark, Nuclear receptor-estradiol complex: A requirement for uterotrophic responses, Endocrinology 95, 174–178 (1974).PubMedGoogle Scholar
  28. 28.
    J. Mester, D. Martel, A. Psychoyos, and E. E. Baulieu, Hormonal control of oestrogen receptor in uterus and receptivity for ovoimplantation in the rat, Nature (London) 250, 776–778 (1974).Google Scholar
  29. 29.
    A. J. W. Hsueh, E. J. Peck Jr., and J. H. Clark, Progesterone antagonism of the oestrogen receptor and oestrogen-induced uterine growth, Nature (London) 254, 337–339 (1975).Google Scholar
  30. 30.
    A. J. W. Hseuh, E. J. Peck Jr., and J. H. Clark, Control of uterine estrogen receptor levels by progesterone, Endocrinology 98, 438–444 (1976).Google Scholar
  31. 31.
    J. C. Heuson, C. Waelbroeck, N. Legros, G. Gallex, C. Robyn, and M. L. Hermite, Inhibition of DMBA-induced mammary carcinogenesis in the rat by 2-Br-α-ergocryptine (CB 154), an inhibitor of prolactin secretion, and by nafoxidine (U-11,100A), an estrogen antagonist, Gynecol. Invest. 2, 130–137 (1971/1972).Google Scholar
  32. 32.
    D. C. Tormey, R. M. Simon, M. E. Lippman, J. M. Bull, and C. E. Myers, Evaluation of tamoxifen dose in advanced breast cancer: A progress report, Cancer Treatment Rep. 60, 1451–1459 (1976).Google Scholar
  33. 33.
    K. D. Schulz, S. August, K. Gasde, and G. Kramer, Studies on the anti-oestrogenic and oestrogen-like action of clomiphene citrate in animal experiments, Gynecol. Invest. 3, 135–141 (1972).PubMedGoogle Scholar
  34. 34.
    B. S. Katzenellenbogen, Synthesis and inducibility of the uterine estrogen-induced protein, IP, during the rat estrous cycle: Clues to uterine estrogen sensitivity, Endocrinology 96, 289–297 (1975).PubMedGoogle Scholar
  35. 35.
    E. J. Peck Jr., J. Burgner, and J. H. Clark, Estrophilic binding sites of the uterus: Relation to uptake and retention of estradiol in vitro, Biochemistry 12, 4596–4603 (1973).PubMedGoogle Scholar
  36. 36.
    E. Milgrom, M. Atger, and E. E. Baulieu, Studies on estrogen entry into uterine cells and on estradiol receptor complex attachment to the nucleus—Is the entry of estrogen into uterine cells a protein-mediated process?, Biochem. Biophys. Acta 320, 267–283 (1973).PubMedGoogle Scholar
  37. 37.
    R. J. B. King and W. I. P. Mainwaring, Steroid-Cell Interactions, pp. 190–262, University Park Press, Baltimore (1974).Google Scholar
  38. 38.
    G. C. Chamness and W. L. McGuire, Estrogen receptor in the rat uterus: Physiological forms and artifacts, Biochemistry 11, 2466–2472 (1972).PubMedGoogle Scholar
  39. 39.
    A. C. Notides and S. Nielsen, The molecular mechanism of the in vitro 4 S to 5 S transformation of the uterine estrogen receptor, J. Biol. Chem. 249, 1866–1873 (1974).PubMedGoogle Scholar
  40. 40.
    E. V. Jensen and E. R. DeSombre, Mechanism of action of the female sex hormones, Annu. Rev. Biochem. 41, 203–230 (1972).PubMedGoogle Scholar
  41. 41.
    K. R. Yamamoto, On the specificity of the binding of the estradiol receptor protein to deoxyribonucleic acid, J. Biol. Chem. 249, 7068–7075 (1974).PubMedGoogle Scholar
  42. 42.
    G. A. Puca and F. Bresciani, Receptor molecules for oestrogens from rat uterus, Nature (London) 218, 967–969 (1968).Google Scholar
  43. 43.
    E. V. Jensen, T. Suzuki, T. Kawashima, W. E. Stumpf, P. W. Jungblut, and E. R. DeSombre, A two step mechanism for the interaction of estradiol with rat uterus, Proc. Natl. Acad. Sci. U.S.A. 59, 632–638 (1968).PubMedPubMedCentralGoogle Scholar
  44. 44.
    D. T. Zava, G. C. Chamness, K. B. Horwitz, and W. L. McGuire, Human breast cancer: Biologically active estrogen receptor in the absence of estrogen?, Science 197, 663–664 (1977).Google Scholar
  45. 45.
    D. T. Zava and W. L. McGuire, Unoccupied sites in nuclei of a breast tumor cell line, J. Biol. Chem. 252, 3703–3708 (1977).PubMedGoogle Scholar
  46. 46.
    G. Sonnenschein, A. M. Soto, J. Cologiore, and R. Farookhi, Estrogen target cells: Establishment of a cell line derived from the rat pituitary tumor MtT/F4, Exp. Cell Res. 101, 15–22 (1976).PubMedGoogle Scholar
  47. 47.
    R. Garola and W. L. McGuire, An improved assay for nuclear estrogen receptor in experimental and human breast cancer, Cancer Res. 37, 3333–3337 (1977).PubMedGoogle Scholar
  48. 48.
    R. Garola and W. L. McGuire, Estrogen receptor and proteolytic activity in human breast tumor nuclei, Cancer Res. 37, 3329–3332 (1977).PubMedGoogle Scholar
  49. 49.
    D. O. Toft, The interaction of uterine estrogen receptors with DNA, J. Steroid Biochem. 3, 515–522 (1972).PubMedGoogle Scholar
  50. 50.
    R. J. B. King and J. Gordon, Involvement of DNA in the receptor mechanism for uterine estradiol receptors, Nature (London) New Biol. 240, 185–186 (1972).Google Scholar
  51. 51.
    T. C. Spelsberg, A. W. Steggles, and B. W. O’Malley, Progesterone binding components of chick oviduct. III. Chromatin acceptor sites, J. Biol. Chem. 246, 4188–4197 (1971).PubMedGoogle Scholar
  52. 52.
    T. Liang and S. Liao, Association of the uterine 17ß-estradiol receptor complex with ribonucleoprotein in vitro and in vivo, J. Biol. Chem. 249, 4671–4678 (1974).PubMedGoogle Scholar
  53. 53.
    V. Jackson and G. R. Chalkley, The binding of estradiol 17/3 to the bovine endometrial nuclear membrane, J. Biol Chem. 249, 1615–1627 (1974).PubMedGoogle Scholar
  54. 54.
    W. T. Schrader, D. O. Toft, and B. W. O’Malley, Progesterone-binding protein of chick oviduct. VI. Interaction of purified progesterone-receptor components with nuclear constituents, J. Biol. Chem. 247, 2401–2407 (1972).PubMedGoogle Scholar
  55. 55.
    G. Giannopoulos and J. Gorski, Estrogen receptors: Quantitative studies on transfer of estradiol from cytoplasmic to nuclear binding sites, J. Biol. Chem. 246, 2524–2529 (1971).PubMedGoogle Scholar
  56. 56.
    J. N. Anderson, E. J. Peck Jr., and J. H. Clark, Estrogen-induced uterine responses and growth: Relationship to receptor estrogen binding by uterine nuclei, Endocrinology 96, 160–167 (1975).PubMedGoogle Scholar
  57. 57.
    M. Sarff and J. Gorski, Control of estrogen binding protein concentration under basal conditions and after estrogen administration, Biochemistry 10, 2557–2563 (1971).PubMedGoogle Scholar
  58. 58.
    A. Matsuzawa and T. Yamamoto, Inhibited growth in vivo of a mouse pregnancy-dependent mammary tumor (TPDMT-4) by an antiestrogen, 2 alpha, 3 alpha-epithio-5 alpha-androstan-17 beta-ol (10275-S), Cancer Res. 36, 1598–1606 (1976).PubMedGoogle Scholar
  59. 59.
    R. I. Nicholson and M. P. Golder, The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary tumours, Eur.J. Cancer 11, 571–579 (1975).PubMedGoogle Scholar
  60. 60.
    M. P. Golder, M. E. A. Phillips, D. R. Fahmy, P. E. Preece, V. Jones, J. H. Henks, and K. Griffiths, Plasma hormones in patients with advanced breast cancer treated with tamoxifen, Eur. J. Cancer 12, 719–723 (1976).PubMedGoogle Scholar
  61. 61.
    A. Manni, J. Trujillo, J. S. Marshall, and O. H. Pearson, Antiestrogen-induced remissions in stage IV breast cancer, Cancer Treatment Rep. 60, 1445–1450 (1976).Google Scholar
  62. 62.
    V. C. Jordan and S. Koerner, Tamoxifen as an anti-tumor agent: Role of oestradiol and prolactin, J. Endocrinol. 68, 305–311(1976).PubMedGoogle Scholar
  63. 63.
    K. J. Willis, D. R. London, H. W. Ward, W. R. Butt, S. S. Lynch, and B. T. Rudd, Recurrent breast cancer treated with the antiestrogen tamoxifen: Correlation between hormonal changes and clinical course, Br. Med. J. 1, 425–428 (1977).PubMedPubMedCentralGoogle Scholar
  64. 64.
    P. A. Kelly, J. Asselin, M. G. Caron, F. Labrie, and J. P. Raynaud, Potent inhibitory effect of a new antiestrogen (RU 16117) on the growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors, J. Natl. Cancer Inst. 58, 623–628 (1977).PubMedGoogle Scholar
  65. 65.
    H. J. Lerner, P. R. Baud, L. Israel, and B. S. Leung, Phase II study of tamoxifen: Report of 74 patients with Stage IV breast cancer, Cancer Treatment Rep. 60, 1431–1435 (1976).Google Scholar
  66. 66.
    D. C. Tormey, R. M. Simon, M. E. Lippman, J. H. Bull, and C. E. Myers, Evaluation of tamoxifen dose in advanced breast cancer: A progress report, Cancer Treatment Rep. 60, 1451–1459 (1976).Google Scholar
  67. 67.
    S. G. Richardson and E. Killen, Metabolism of oestradiol by human mammary tumor 800 x g supernatants pretreated with dihydrolipoic acid, Cancer Lett. 2, 299–304 (1977).PubMedGoogle Scholar
  68. 68.
    W. Levin, R. M. Welch, and A. H. Cormey, Decreased uterotrophic potency of oral contraceptives in rats pretreated with phénobarbital, Endocrinology 83, 149–156, 1968.PubMedGoogle Scholar
  69. 69.
    W. Levin, R. M. Welch, and A. H. Cormey, Effect of phénobarbital and other drugs on the metabolism and uterotrophic action of estradiol 17-ß and estrone, J. Pharmacol. Exp. Ther. 159, 361–371 (1968).Google Scholar
  70. 70.
    S. G. Korenman, Relation between estrogen inhibitory activity and binding to cytosol of rabbit and human uterus, Endocrinology 87, 1119–1123 (1970).Google Scholar
  71. 71.
    S. G. Korenman, Comparative binding affinity of estrogens and its relation to estrogenic potency, Steroids 13, 163–177 (1969).PubMedGoogle Scholar
  72. 72.
    J. A. Cidlowski and T. G. Muldoon, Dissimilar effects of antiestrogens upon estrogen receptors in responsive tissues of male and female rats, Biol. Reprod. 15, 381–389 (1976).PubMedGoogle Scholar
  73. 73.
    H. Rochefort and F. Capony, Binding properties of an anti-estrogen to the estradiol receptor of uterine cytosol, FEBS Lett. 20, 11–15 (1972).Google Scholar
  74. 74.
    L. Terenius, Two modes of interaction between oestrogen and anti-oestrogen, Acta Endocrinol. 64, 47–58 (1970).PubMedGoogle Scholar
  75. 75.
    C. Martucci and J. Fishman, Uterine estrogen receptor binding of catecholestrogens and of estetrol [l,3,5,(10)-estratriene-3,15α,16α,17ß-tetrol], Steroids 27,325–333 (1976).PubMedGoogle Scholar
  76. 76.
    L. J. Black and R. J. Kraay, Evaluation of two types of estrogen inhibition with regard to effects on uptake and binding of 3H-ß-estradiol in the uterus, J. Steroid Biochem. 4, 467–475 (1973).PubMedGoogle Scholar
  77. 77.
    R. Hahnel, E. Twaddle, and T. Ratajczak, The influence of synthetic antiestrogens on the binding of tritiated estradiol-17ß by cytosols of human uterus and human breast carcinoma, J. Steroid Biochem. 4, 687–695 (1973).PubMedGoogle Scholar
  78. 78.
    M. Lippman, G. Bolan, and K. Huff, Interactions of antiestrogens with human breast cancer in long term tissue culture, Cancer Treatment Rep. 60, 1421–1429 (1976).Google Scholar
  79. 79.
    W. Powell-Jones, P. Davies, and K. Griffiths, Influence of antiestrogens on specific binding of 3H-ß-oestradiol in vitro by nuclei from rat mammary tumors, J. Endocrinol. 66, 437–138 (1975).PubMedGoogle Scholar
  80. 80.
    V. C. Jordan and S. Koerner, Tamoxifen (ICI 46,474) and the human carcinoma 8 S oestrogen receptor, Eur. J. Cancer 11, 205–206 (1975).PubMedGoogle Scholar
  81. 81.
    H. Rochefort and F. Capony, Estradiol dependent decrease of binding inhibition by antiestrogens (a possible test of receptor activation), Biochem. Biophys. Res. Commun. 75, 277–285 (1977).PubMedGoogle Scholar
  82. 82.
    F. Capony and H. Rochefort, In vitro and in vivo interactions of 3H-dimethylstilbestrol with the estrogen receptor, Mol. Cell. Endocrinol. 8, 47–64 (1977).PubMedGoogle Scholar
  83. 83.
    R. W. Turnell, N. Kaiser, R. J. Milholland, and F. Rosen, Glucocorticoid receptors in rat thymocytes: Interactions with the antiglucocorticoid cortexolone and mechanism of its action, J. Biol. Chem. 249, 1133–1138 (1974).PubMedGoogle Scholar
  84. 84.
    E. R. DeSombre, S. Mohla, and E. V. Jensen, Receptor transformation, they key to estrogen action, J. Steroid Biochem. 6, 469–473 (1975).PubMedGoogle Scholar
  85. 85.
    H. Rochefort, F. Lignon, and F. Capony, Effect of antiestrogens on uterine estradiol receptors, Gynecol. Invest. 3, 43–62 (1972).PubMedGoogle Scholar
  86. 86.
    H. H. Samuels and G. M. Tomkins, Relation of steriod structure to enzyme induction in hepatoma tissue culture cells, J. Mol. Biol. 52, 57–74 (1970).PubMedGoogle Scholar
  87. 87.
    G.G. Rousseau, Interaction of steriods with hepatoma cells: Molecular mechanisms of glucocorticoid hormone action, J. Steroid Biochem. 6, 75–89 (1975).PubMedGoogle Scholar
  88. 88.
    T. S. Ruh and M. F. Ruh, The effect of antiestrogens on the nuclear binding of the estrogen receptor, Steroids 24, 209–224 (1974).PubMedGoogle Scholar
  89. 89.
    J. H. Clark, Z. Paszko, and E. J. Peck Jr., Nuclear binding and retention of the receptor estrogen complex: Relation to the agonistic and antagonistic properties of estriol, Endocrinology 100, 91–96 (1977).PubMedGoogle Scholar
  90. 90.
    Y. Koseki, D. T. Zava, G. C. Chamness, and W. L. McGuire, Estrogen receptor translocation and replenishment by the antiestrogen tamoxifen, Endocrinology 101, 1104–1110 (1977).PubMedGoogle Scholar
  91. 91.
    T. S. Ruh and L. J. Baudendistel, Different nuclear binding sites for antiestrogen and estrogen receptor complexes, Endocrinology 100, 420–126 (1977).PubMedGoogle Scholar
  92. 92.
    J. Anderson, J. H. Clark, and E. J. Peck Jr., Oestrogen and nuclear binding sites: Determination of specific sites by 3Hß oestradiol exchange, Biochem. J. 126, 561–567 (1972).PubMedPubMedCentralGoogle Scholar
  93. 93.
    D. T. Zava, N. Y. Harrington, and W. L. McGuire, Nuclear estradiol receptor in the adult rat uterus: A new exchange assay, Biochemistry 15, 4292–4297 (1976).PubMedGoogle Scholar
  94. 94.
    J. N. Anderson, E. J. Peck Jr., and J. H. Clark, Nuclear receptor-estrogen complex: Relationship between concentration and early uterotrophic responses, Endocrinology 92, 1488–1495 (1973).PubMedGoogle Scholar
  95. 95.
    J. S. Rinehart, T. S. Ruh, and M. S. Ruh, Antiestrogen action: Uterine nuclear retention of the CI-628 antiestrogen receptor complexes in vitro, Acta Endocrinol. 84, 367–373 (1977).Google Scholar
  96. 96.
    C. M. Szego and S. Roberts, Steroid action and interaction in uterine metabolism, Recent Prog. Horm. Res. 8, 419–469 (1953).Google Scholar
  97. 97.
    F. L. Hisaw, Comparative effectiveness of estrogens on fluid imbibition and growth of the rat’s uterus, Endocrinology 64, 276–289 (1959).PubMedGoogle Scholar
  98. 98.
    J. Gorski, Estrogen binding and control of gene expression in the uterus, in: Handbook of Physiology, Endocrinology II, Part 1 (R.O. Greep, ed.), pp. 525–536, American Physiology Society, Washington D.C. (1973).Google Scholar
  99. 99.
    T. H. Hamilton, Isotopic studies on estrogen-induced accelerations of ribonucleic acid and protein synthesis, Proc. Natl. Acad. Sci. U.S.A. 49, 373–379 (1963).PubMedPubMedCentralGoogle Scholar
  100. 100.
    T. S. Ruh, B. S. Katzenellenbogen, J. A. Katzenellenbogen, and J. Gorski, Estrone interaction with the rat uterus: In vitro response and nuclear uptake, Endocrinology 92, 125–134 (1973).PubMedGoogle Scholar
  101. 101.
    F. Stormshak, R. Leake, N. Wertz, and J. Gorski, Stimulatory and inhibitory effects of estrogen on uterine DNA synthesis, Endocrinology 99, 1501–1511 (1976).PubMedGoogle Scholar
  102. 102.
    J. H. Clark and E. J. Peck Jr., Nuclear retention of receptor-estrogen complex and nuclear acceptor sites, Nature (London) 260, 635–637 (1976).Google Scholar
  103. 103.
    J. Mester and E. E. Baulieu, Dynamics of oestrogen-receptor distribution between the cytosol and nuclear fractions of immature rat uterus after oestradiol administration, Biochem. J. 146, 617–623 (1975).PubMedPubMedCentralGoogle Scholar
  104. 104.
    J. V. Juliano and G. H. Stancel, Estrogen receptors in the rat uterus: Retention of hormone-receptor complexes, Biochemistry 15, 916–920 (1976).PubMedGoogle Scholar
  105. 105.
    L. J. Baudendistel and T. S. Ruh, Antiestrogen action: Differential nuclear retention and extractability of the estrogen receptor, Steroids 28, 223–237 (1976).PubMedGoogle Scholar
  106. 106.
    V. C. Jordan, C. J. Dix, L. Rowsby, and G. Prestwich, Studies on the mechanism of action of the nonsteroidal antiestrogen tamoxifen (ICI 46,474) in the rat, Mol. Cell. Endocrinol. 7, 177–192 (1977).PubMedGoogle Scholar
  107. 107.
    J. M. Sala-Trepat and E. Reti, Dissociation studies of different forms of the estradiol-receptor complex from calf uterus: Higher stability of the complex bound to chromatin, Biochem. Biophys. Acta 338, 92–103 (1974).Google Scholar
  108. 108.
    R. De Hertogh, E. Ekka, I. Vanderheyden, and J. J. Hoet, Slowly exchangeable pool of estradiol in the rat uterus, J. Steroid Biochem. 4, 313–320 (1973).PubMedGoogle Scholar
  109. 109.
    Y. S. Cho-Chung and B. H. Redler, Dibutyryl cyclic AMP mimics ovariectomy: Nuclear protein phosphorylation in mammary tumor regression, Science 197, 272–275 (1977).PubMedGoogle Scholar
  110. 110.
    S. M. Paul and P. Skolnik, Catechol oestrogens inhibit oestrogen elicited accumulation of hypothalamic cyclic AMP suggesting role as endogenous antiestrogens, Nature (London) 266, 559–561 (1977).Google Scholar
  111. 111.
    E. B. Thompson and M. E. Lippman, Mechanism of action of glucocorticoids, Metab. Clin. Exp. 23, 159–202 (1974).PubMedGoogle Scholar
  112. 112.
    J. Meites, Relation of prolactin and estrogen to mammary tumorigenesis in the rat, J. Natl. Cancer Inst. 48, 1217–1224 (1972).PubMedGoogle Scholar
  113. 113.
    D. Medina, Tumor formation in preneoplastic mammary nodule lines in mice treated with nafoxidine, testoterone, and 2-bromo-alpha-ergocryptine, J. Natl. Cancer Inst. 58, 1107–1110 (1977).PubMedGoogle Scholar
  114. 114.
    J. Richards and D. R. Griffith, Effects of as- and trans-clomiphene on mammary gland development in the rat, Fertil. Steril 25, 74–78 (1974).PubMedGoogle Scholar
  115. 115.
    G. Bedes, The effect of chlormadione acetate upon estradiol uptake by the rat mammary gland in organ culture, Am. J. Obstet. Gynecol. 188, 1050–1053 (1974).Google Scholar
  116. 116.
    C. Huggins, R. C. Moon, and S. Morii, Extinction of experimental mammary cancer. I. Estradiol 17-ß and progesterone, Proc. Natl. Acad. Sci. U.S.A. 48, 379–386 (1962).PubMedPubMedCentralGoogle Scholar
  117. 117.
    G. S. Kledzik, C. J. Bradley, S. Marshall, G. A. Campbell, and J. Meites, Effects of high doses of estrogen on prolactin-binding activity and growth of carcinogen-induced mammary cancers in rats, Cancer Res. 36, 3265–3268 (1976).PubMedGoogle Scholar
  118. 118.
    J. Meites, E. Cassell, and J. Clark, Estrogen inhibition of mammary tumor growth in rats: Counteraction by prolactin, Proc. Soc. Exp. Biol. Med. 137, 1225–1227 (1971).PubMedGoogle Scholar
  119. 119.
    K. B. Horwitz and W. L. McGuire, Progesterone and progesterone receptors in experimental breast cancer, Cancer Res. 37, 1722–1738 (1977).Google Scholar
  120. 120.
    B. S. Leung and G. H. Sasaki, On the mechanism of prolactic and estrogen action in 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in the rat. II. In vivo tumor responses and estrogen receptors, Endocrinology 97, 564–572 (1975).PubMedGoogle Scholar
  121. 121.
    J. H. Clark and S. McCormack, Clomid or nafoxidine administered to neonatal rats causes reproductive tract abnormalities, Science 197, 164–165 (1977).PubMedGoogle Scholar
  122. 122.
    D. C. Poskanzer and A. L. Herbst, Epidemiology of vaginal adenosis and adenocarcinoma associated with exposure to stilbestrol in utero, Cancer 39, 1892–1895 (1977).Google Scholar
  123. 123.
    V. C. Jordan, Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata, Eur. J. Cancer 12, 419–424 (1976).PubMedGoogle Scholar
  124. 124.
    F. Labrie, P. A. Kelly, J. Asselin, and J. P. Raynaud, Potent inhibitory activity of a new antiestrogen, RU 16,117, on the development and growth of DMBA-induced rat mammary adenocarcinoma, Recent Results Cancer Res. 57, 109–120.Google Scholar
  125. 125.
    P. A. Kelly, J. Asselin, M. G. Caron, J. P. Raynaud, and F. Labrie, High inhibitory activity of a new antiestrogen, RU 16117 (11 alpha-methoxy ethinyl estradiol), on the development of dimethylbenz(a)anthracene-induced mammary tumors, Cancer Res. 37, 76–81 (1977).PubMedGoogle Scholar
  126. 126.
    T. L. Tsai and B. S. Katzenellenbogen, Antagonism of development and growth of 7,12 dimethylbenz(a)anthracene-induced rat mammary tumors by the antiestrogen U23,469 and effects on estrogen and progesterone receptors, Cancer Res. 37, 1537–1543 (1977).PubMedGoogle Scholar
  127. 127.
    L. Terenius, Effect of anti-oestrogens on initiation of mammary cancer in the female rat, Cancer 7, 65–70 (1971).Google Scholar
  128. 128.
    O. H. Pearson, O. Llerena, L. Llerena, A. Molina, and T. Butler, Prolactin-dependent rat mammary cancer: A model for man?, Trans. Assoc. Am. Physicians 82, 225–238 (1969).PubMedGoogle Scholar
  129. 129.
    A. Sterental, J. M. Dominguez, C. Weissman, and O. H. Pearson, Pituitary role in the estrogen dependency of experimental mammary cancer, Cancer Res. 23, 481–485 (1963).PubMedGoogle Scholar
  130. 130.
    H. Nagasawa and R. Yanai, Effects of prolactin or growth hormone on growth of carcinogen-induced mammary tumors of adeno-ovariectomized rats, Int. J. Cancer 6, 488–495 (1970).PubMedGoogle Scholar
  131. 131.
    W. L. McGuire, G. C. Chamness, M. E. Costlow, and K. B. Horwitz, in: Hormone Receptors in Breast Cancer (G. S. Levy, ed.), pp. 265–299, Marcel Dekker, New York (1976).Google Scholar
  132. 132.
    A. Manni, J. E. Trujillo, and O. H. Pearson, Predominant role of prolactin in stimulating the growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumor, Cancer Res. 37, 1216–1219 (1977).PubMedGoogle Scholar
  133. 133.
    L. Terenius, Anti-oestrogens and breast cancer, Eur. J. Cancer 7, 57–64 (1971).PubMedGoogle Scholar
  134. 134.
    G. Gallez, J. C. Heuson, and C. Waelbroeck, Growth stimulating effect of nafoxidine on rat mammary tumor after ovariectomy, Eur. J. Cancer 9, 699–700 (1973).PubMedGoogle Scholar
  135. 135.
    V. C. Jordan and S. Koerner, Tamoxifen as an antitumor agent: Role of oestradiol and prolactin, J. Endocrinol 68, 305–311 (1976).PubMedGoogle Scholar
  136. 136.
    V. C. Jordan and T. Jaspan, Tamoxifen as an anti-tumor agent: Oestrogen binding as a predictive test for tumor response, J. Endocrinol. 68, 453–460 (1976).PubMedGoogle Scholar
  137. 137.
    E. R. DeSombre and L. Y. Arbogast, Effect of the antiestrogen CI 628 on the growth of rat mammary tumors, Cancer Res. 34, 1971–1976 (1974).PubMedGoogle Scholar
  138. 138.
    R. I. Nicholson and M. P. Golder, The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary tumor, Eur. J. Cancer 11, 571–579 (1975).PubMedGoogle Scholar
  139. 139.
    P. A. Kelly, J. Asselin, M. C. Caron, F. Labrie, and J.-P. Raynaud, Potent inhibitory effect of a new antiestrogen (RU 16117) on the growth of 7,12-dimethylbenz(a)-anthracene induced rat mammary tumors, J. Natl. Cancer Inst. 58, 623–628 (1977).PubMedGoogle Scholar
  140. 140.
    D. P. Griswold Jr., and C. H. Green, Observation on the hormone sensitivity of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the Sprague-Dawley rat, Cancer Res. 30, 819–826 (1970).PubMedGoogle Scholar
  141. 141.
    C. J. Bradley, G. S. Kledzik, and J. Meites, Prolactin and estrogen dependency of rat mammary cancers at early and late stages of development, Cancer Res. 36, 319–324 (1976).PubMedGoogle Scholar
  142. 142.
    K. D. Schulz, B. Haselmayer, and F. Holzel, The influence of clomid and its isomers on dimethyl benzathracene-induced rat mammary tumors, in: Basic Actions of Sex Steroids on Target Organs, pp. 274–279, Karger, Basel (1971).Google Scholar
  143. 143.
    W. L. McGuire and J. Julian, Comparison of macromolecular binding of estradiol in hormone-dependent and hormone-independent rat mammary carcinomata, Cancer Res. 31, 1440–1445 (1971).PubMedGoogle Scholar
  144. 144.
    E. R. DeSombre, G. Kledzik, S. Marshall, and J. Meites, Estrogen and prolactin receptor concentrations in rat mammary tumors and response to endocrine ablation, Cancer Res. 36, 354–358 (1976).PubMedGoogle Scholar
  145. 145.
    I. M. Holdaway and H. G. Friesen, Correlation between hormone binding and growth response of rat mammary tumor, Cancer Res. 36, 1562–1567 (1976).PubMedGoogle Scholar
  146. 146.
    W. L. McGuire, P. P. Carbone, M. E. Sears, and G. C. Escher, Estrogen receptors in human breast cancer: An overview, in: Estrogen Receptors in Human Breast Cancer (W. L. McGuire, P. P. Carbone, and E. P. Vollmer, eds.), pp. 1–7, Raven Press, New York (1975).Google Scholar
  147. 147.
    V. C. Jordan and L. J. Dowse, Tamoxifen as an anti-tumor agent: Effect on oestrogen binding, J. Endocrinol. 68, 297–303 (1976).PubMedGoogle Scholar
  148. 148.
    W. Powell-Jones, D. A. Jenner, R. W. Blarney, P. Davies, and K. Griffiths, Influence of anti-oestrogens on the specific binding in vitro of 3H-ß-oestradiol by cytosol of rat mammary tumours, Biochem. J. 150, 71–75 (1975).PubMedPubMedCentralGoogle Scholar
  149. 149.
    R. I. Nicholson, M. P. Golder, P. Davies, and K. Griffiths, Effect of oestradiol-17ß and tamoxifen on total and accessible cytoplasmic oestradiol-17ß receptors in DMBA-induced rat mammary tumours, Eur. J. Cancer 12, 711–717 (1976).PubMedGoogle Scholar
  150. 150.
    R. I. Nicholson, P. Davies, and K. Griffiths, Effects of oestradiol-17ß and tamoxifen on nuclear oestradiol-17ß receptors in DMBA-induced rat mammary tumors, Eur. J. Cancer 13, 201–208 (1977).PubMedGoogle Scholar
  151. 151.
    M. Callantine, Nonsteroidal estrogen antagonists, Clin. Obstet. Gynecol. 10, 74–87 (1967).PubMedGoogle Scholar
  152. 152.
    S. Roy, V. B. Manesh, and R. B. Greenblatt, Effects of clomiphene on the physiology of reproduction in the rat. I. Changes in the hypophyseal-gonadal axis, Acta Endocrinol. 47, 645–656 (1964).PubMedGoogle Scholar
  153. 153.
    G. W. Duncan and A. D. Forbes, Blastocyst survival and nidation in rats treated with oestrogen antagonists, J. Reprod. Fertil. 10, 161–167 (1965).PubMedGoogle Scholar
  154. 154.
    G. V. Groom and K. Griffiths, Effect of the antiestrogen tamoxifen on plasma levels of luteinizing hormone, follicle-stimulating hormone, prolactin, oestradiol, and progesterone in normal pre-menopausal women, J. Endocrinol. 70, 421–428 (1976).PubMedGoogle Scholar
  155. 155.
    F. Comhaire, Treatment of oligospermia with tamoxifen, Int. J. Fertil. 21, 232–238 (1976).Google Scholar
  156. 156.
    L. R. Morgan Jr., P. S. Schein, P. V. Woolley, D. Hoth, J. Macdonald, M. Lippman, L. E. Posey, and R. W. Beazley, Therapeutic use of tamoxifen in advanced breast cancer: Correlation with biochemical parameters, Cancer Treatment Rep. 60, 1437–1443 (1976).Google Scholar
  157. 157.
    E.O.R.T.C. Breast Cancer Group, Clinical trial of nafoxidine, an oestrogen antagonist in advanced breast cancer, Eur. J. Cancer 8, 387–389 (1972).Google Scholar
  158. 158.
    H. J. G. Bloom and E. Boesen, Antiestrogens in treatment of breast cancer: Value of nafoxidine in 52 advanced cases, Br. Med. J. 2, 7–10 (1974).PubMedPubMedCentralGoogle Scholar
  159. 159.
    G. H. Sasaki, B. S. Leung, and W. S. Fletcher, Therapeutic use of nafoxidine in advanced breast cancer—A correlation with endocrine ablation and tumor estrogen response, Proc. Am. Soc. Clin. Oncol. 16, 271 (1975).Google Scholar
  160. 160.
    H. W. C. Ward, Antiestrogen therapy for breast cancer: A trial of tamoxifen at two dose levels, Br. Med. J. 1, 13–14 (1973).PubMedPubMedCentralGoogle Scholar
  161. 161.
    J. M. Fromson, S. Pearson, and S. Bramali, The metabolism of tamoxifen (ICI 46,474). II. In female patients, Xenobiotica 3, 711–714 (1973).Google Scholar
  162. 162.
    R. Garola, C. M. Levy, I. Vegh, C. Magin, J. C. Martinez, and E. Hecker, In vivo blockade of the estradiol-binding protein (EBP) by clomiphene citrate in human breast cancer, Oncology 30, 105–112 (1974).Google Scholar
  163. 163.
    E. Hecker, I. Vegh, C. M. Levy, C. A. Magin, J. C. Martinez, J. Loureiro, and R. E. Garola, Clinical trial of clomiphene in advanced breast cancer, Eur. J. Cancer 10, 747–749 (1974).PubMedGoogle Scholar
  164. 164.
    L. R. Morgan, P. S. Schein, D. Hoth, J. McDonal, L. E. Posey, R. W. Beazley, and L. Trench, Therapeutic use of tamoxifen in advanced breast cancer: Correlation with biochemical parameters, Proc. Am. Soc. Cancer Res. 17, 126 (1976).Google Scholar
  165. 165.
    H. P. Cole, C. T. A. Jones, and I. D. H. Todd, A new anti-oestrogenic agent in late breast cancer: An early clinical appraisal of ICI 46,474, Br. J. Cancer 25, 270–274 (1971).PubMedPubMedCentralGoogle Scholar
  166. 166.
    M. J. O’Halloran and P. G. Maddock, ICI 46,474 in breast cancer, J. Ir. Med. Assoc. 67, 38–39 (1974).PubMedGoogle Scholar
  167. 167.
    J. C. Heuson, Current overview of E.O.R.T.C. clinical trials with tamoxifen, Cancer Treatment Rep. 60, 1463–1466 (1976).Google Scholar
  168. 168.
    S. Legha and F. M. Muggia, Antiestrogens in the treatment of cancer, Ann. Intern Med. 84, 751 (1976).PubMedGoogle Scholar
  169. 169.
    M. C. Macnaughton, Treatment of female infertility, in: Clinics in Endocrinology (J- A. Loraine, ed.), pp. 545–560, W. B. Saunders, London (1973).Google Scholar
  170. 170.
    H. D. Soule, J. Vasquez, A. Long, S. Albert, and M. Brennan, A human cell line from a pleural effusion derived from a breast carcinoma, J. Natl. Cancer Inst. 51, 1409–1416 (1973).PubMedGoogle Scholar
  171. 171.
    S. C. Brooks, E. R. Locke, and H. D. Soule, Estrogen receptor in a human cell line (MCF-7) from breast carcinoma, J. Biol. Chem. 248, 6251–6253 (1973).PubMedGoogle Scholar
  172. 172.
    K. B. Horwitz, M. E. Costlow, and W. L. McGuire, MCF-7: A human breast cancer cell line with estrogen, androgen, progesterone and glucocorticoid receptors, Steroids 26, 785–795 (1975).PubMedGoogle Scholar
  173. 173.
    M. E. Lippman and G. Bolan, Oestrogen-responsive human breast cancer in long term tissue culture, Nature (London) 256, 592–593 (1975).Google Scholar
  174. 174.
    A. W. Steggles and R. J. B. King, The use of protamine to study 6,7–3H oestradiol-17ß binding in rat uterus, Biochem. J. 118, 695–701 (1970).PubMedPubMedCentralGoogle Scholar
  175. 175.
    G. C. Chamness, K. Huff, and W. L. McGuire, Protamine-precipitated estrogen receptor: A solid phase ligand exchange assay, Steroids 25, 627–635 (1975).PubMedGoogle Scholar
  176. 176.
    E. Milgrom, L. Thi, M. Atger, and E.-E. Baulieu, Mechanisms regulating the concentration and the conformation of progesterone receptors in the uterus,J. Biol. Chem. 247, 8000–8004 (1972).Google Scholar
  177. 177.
    K. B. Horwitz, W. L. McGuire, O. H. Pearson, and A. Segaloff, Predicting resonse to endocrine therapy in human breast cancer: A hypothesis, Science 189, 726–727 (1975).PubMedGoogle Scholar
  178. 178.
    W. W. Leavitt, T. J. Chen, and T. C. Allen, Regulation of progesterone receptor formation by estrogen action, Ann. N. Y. Acad. Sci. 286, 210–225 (1977).PubMedGoogle Scholar
  179. 179.
    K. Burton, A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid, Biochem. J. 62, 315–323 (1956).PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1978

Authors and Affiliations

  • Kathryn B. Horwitz
    • 1
  • William L. McGuire
    • 1
  1. 1.Department of MedicineUniversity of Texas Health Science Center at San AntonioSan AntonioUSA

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