Selective Estrogen Modulators as an Anticancer Tool:

Mechanisms of Efficiency and Resistance
  • Surojeet Sengupta
  • V. Craig Jordan
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 630)


The majority of breast cancers are estrogen receptor (ER) positive and depend on estrogen for growth. Therefore, blocking estrogen mediated actions remains the strategy of choice for the treatment and prevention of breast cancer. The selective estrogen receptor modulators (SERMs) are molecules that block estrogen action in breast cancer but can still potentially maintain the beneficial effects of estrogen in other tissues, such as bone and cardiovascular system. Tamoxifen, the prototypical drug of this class has been used extensively for the past 30 years to treat and prevent breast cancer. The target of drug action, ERs alpha and beta, are the two receptors which are responsible for the first step in estrogen and SERM action. The SERM binds to the ERs and confers a unique conformation to the complex. In a target site which expresses antiestrogenic actions, the conformation of the ER is distinctly different from estrogen bound ER. The complex recruits protein partners called corepressors to prevent the transcription of estrogen responsive genes. In contrast, at a predominantly estrogenic site coactivators for estrogen action are recruited. Unfortunately at an antiestrogenic site such as breast cancer, long term SERM therapy causes the development of acquired resistance. The breast and endometrial tumor cells selectively become SERM stimulated. Overexpression of receptor tyro sine kinases, HER-2, EGRF and IGRF and the signaling cascades following their activation are frequently involved in SERM resistant breast cancers. The aberrantly activated PI3K/AKT and MAPK pathways and their cross talk with the genomic components of the ER action are implicated in SERM resistance. Other down stream factors of HER-2 and EGRF signaling, such as PI3K/AKT, MAPK or mTOR pathways has also been found to be involved in resistance mechanisms. Blocking the actions of HER-2 and EGRF represent a rational strategy for treating SERM resistant phenotypes and may in fact restore the sensitivity to the SERMs. Another approach exploits the discovery that low dose estrogen will induce apoptosis in the SERM resistant breast cancers. Numerous clinical studies are addressing these issues.


Breast Cancer Estrogen Receptor Breast Cancer Cell Natl Cancer Inst Athymic Mouse 
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  1. 1.
    Jordan VC. Biochemical pharmacology of antiestrogen action. Pharmacol Rev 1984; 36(4):245–276.PubMedGoogle Scholar
  2. 2.
    Harper MJ, Walpole AL. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil 1967; 13(1):101–119.PubMedGoogle Scholar
  3. 3.
    Harper MJ, Walpole AL. Mode of action of I.C.I. 46,474 in preventing implantation in rats. J Endocrinol 1967; 37(1):83–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Klopper A, Hall M. New synthetic agent for the induction of ovulation: preliminary trials in women. Br Med J 1971; 1(5741):152–154.PubMedCrossRefGoogle Scholar
  5. 5.
    Jordan VC. Prolonged antioestrogenic activity of ICI 46,474 in the ovariectomized mouse. J Reprod Fertil 1975; 42(2):251–258.PubMedGoogle Scholar
  6. 6.
    Lippman M, Bolan G, Huff K. Interactions of antiestrogens with human breast cancer in long-term tissue culture. Cancer Treat Rep 197; 60(10):1421–1429.Google Scholar
  7. 7.
    Jordan VC, Koerner S. Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer 1975; 11(3):205–206.PubMedGoogle Scholar
  8. 8.
    Skidmore J, Walpole AL, Woodburn J. Effect of some triphenylethylenes on oestroadiol binding in vitro to macromolecuules from uterus and anterior pituitary. J Endocrinol 1972; 52(2):289–298.PubMedCrossRefGoogle Scholar
  9. 9.
    Jordan VC. Antiestrogenic and antitumor properties of tamoxifen in labolatory animals. Cancer Treat Rep 1976; 60(10):1409–1419.PubMedGoogle Scholar
  10. 10.
    Jordan VC, Brodie AM. Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer. Steroids 2007; 72(1):7–25.PubMedCrossRefGoogle Scholar
  11. 11.
    Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2003; 2(3):205–213.PubMedCrossRefGoogle Scholar
  12. 12.
    Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998; 351(9114):1451–467.Google Scholar
  13. 13.
    Jordan VC, Collins MM, Rowsby L et al. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 1977;75(2):305–316.PubMedCrossRefGoogle Scholar
  14. 14.
    Allen KE, Clark ER, Jordan VC. Evidence for the metabolic activation of nonsteroidal antioestrogens: a study of structure-activity relationships. Br J Pharmcol 1980; 71(1):83–91.Google Scholar
  15. 15.
    Jordan VC, Murphy CS. Endocrine pharmacology of antiestrogens as antitumor agents. Endocr Rev 1990; 11(4):578–610.PubMedCrossRefGoogle Scholar
  16. 16.
    Shiau AK, Barstad D, Loria PM et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998;97(7):927–937.CrossRefGoogle Scholar
  17. 17.
    Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 1896; 148:104–107, 162–167.CrossRefGoogle Scholar
  18. 18.
    Jensen EV, Jacobson HI. Basic gudie to the mechanism of estrogen action. Recent Progress in Hormone Research 1962; 18:387–414.Google Scholar
  19. 19.
    Jensen EV, Block GE, Smith S et al. Estrogen receptors and breast cancer response to adrenalectomy. Natl Cancer Inst Monogr 1971;34:55–70.PubMedGoogle Scholar
  20. 20.
    Jordan VC, Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 1976; 12(6):419–424.PubMedGoogle Scholar
  21. 21.
    Jordan VC, Koerner S. Tamoxifen as an anti-tumour agent: role of oestradiol and prolactin. J Endocrinol 1976; 68(02):305–311.PubMedCrossRefGoogle Scholar
  22. 22.
    Jordan VC, Dowse LJ. Tamoxifen as an anti-tumour agent: effect of oestrogen binding. J Endocrinol 1976; 68(02):297–303.PubMedCrossRefGoogle Scholar
  23. 23.
    Jordan VC, Jaspan T. Tamoxifen as an anti-tumour agent: oestrogen binding as a predictive test for tumour response. J Endocrinol 1976; 68(3):453–460.PubMedCrossRefGoogle Scholar
  24. 24.
    Nicholson RI, Golder MP. The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary tumours. Eur J Cancer 1975; 11(8):571–579.PubMedGoogle Scholar
  25. 25.
    Jordan VC, Dix CJ, Allen KE. The effectiveness of long term tamoxifen treatment in a laboratory model for adjuvant hormone therapy of breast ancer. In: Salmon SE, Jones SE, eds. Adjuvant Therapy of Cancer. Vol. 2 New York: Grune & Stratton, Inc.; 1979:19–26.Google Scholar
  26. 26.
    Jordan VC, Allen KE. Evaluation of the antitumour activity of the nonsteroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 1980; 16(2):239–251.PubMedGoogle Scholar
  27. 27.
    Osborne CK, Hobbs K, Clark GM. Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Ancer Res 1985; 45(2):584–590.Google Scholar
  28. 28.
    Gottardis MM, Robinson SP, Jordan VC. Estradiol-stimulated growth of MCF-7 tumors implanted in athymic mice: a model to study the tumoristatic action of tamoxifen. J Steroid Biochem 1988; 30(1–6):311–314.PubMedCrossRefGoogle Scholar
  29. 29.
    Kiang DT, Kennedy BJ. Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med 1977; 87(6):687–690.PubMedGoogle Scholar
  30. 30.
    Baum M, Brinkley DM, Dossett JA et al. Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer. Lancet 1983; 2(8374):450.PubMedCrossRefGoogle Scholar
  31. 31.
    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. Early Breast Cancer Trialists’ Collabortaive Group. Lancet 1992; 339(8785):71–85.Google Scholar
  32. 32.
    Fisher B, Dignam J, Bryant J et al. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 191; 93(9):684–690.CrossRefGoogle Scholar
  33. 33.
    Powles TJ, Ashley S, Tidy A et al. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst 2007; 99(4):283–290.PubMedCrossRefGoogle Scholar
  34. 34.
    Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial. Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office 9MRC), Edinburgh. 1987; 2(8552):171–175.Google Scholar
  35. 35.
    Jordan VC. Chemosuppression of breast cancer with tamoxifen: laboratory evidence and future clinical investigations. Cancer Invest 1988; 6(5):589–595.PubMedCrossRefGoogle Scholar
  36. 36.
    Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for the prevention of breast cancer: current status of teh National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005; 97(22):1651–1662.Google Scholar
  37. 37.
    Cuzick J, Forbes J, Edwards R et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 2002; 360(9336):817–824.PubMedCrossRefGoogle Scholar
  38. 38.
    Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90(18):1371–1388.PubMedCrossRefGoogle Scholar
  39. 39.
    Cuzick J, Forbes JF, Sestak I et al. Long-tem results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 2007; 99(4):272–282.PubMedCrossRefGoogle Scholar
  40. 40.
    Buzdar AU, Marcus C, Holmes F et al. Phase II evaluation of Ly156758 in metastatic breast cancer. Oncology 1988; 45(5):344–345.PubMedCrossRefGoogle Scholar
  41. 41.
    Jordan VC, Phelps E, Lindgren JU. Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 1987; 10(1):31–35.PubMedCrossRefGoogle Scholar
  42. 42.
    Gottardis MM, Jordan VC. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res 1987; 47(15):4020–4024.PubMedGoogle Scholar
  43. 43.
    Black LJ, Jones CD, Falcone JF. Antagonism of estrogen action with a new benzothiophen derived atniestrogen. Life Sci 1983; 32(9):1031–1036.PubMedCrossRefGoogle Scholar
  44. 44.
    Gottardis MM, Ricchio ME, Satyaswaroop PG et al. Effect of steroidal adn nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCac101) in athymic mice. Cancer Res 1990; 50(11):3189–3192.PubMedGoogle Scholar
  45. 45.
    Lerner LJ, Jordan VC. The development of antiestrogens for the treatment of breast cancer. Cancer Res 1990; 50:4177–4189.PubMedGoogle Scholar
  46. 46.
    Cummings SR, Eckert S, Krueger KA 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(23):2189–2197.PubMedCrossRefGoogle Scholar
  47. 47.
    Jordan VC. Optimising endocrine approaches for the chemoprevention of breast cancer beyond the Study of Tamoxifen and Raloxifene (STAR) trial. Eur J Cancer 2006; 42(17):2909–29123.PubMedCrossRefGoogle Scholar
  48. 48.
    Vogel VG, Costantino JP, Wickerham DL et al. Effects of tamoxifen vs 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(23):2727–2741.PubMedCrossRefGoogle Scholar
  49. 49.
    Jordan VC. Chemoprevention of breast cancer with selective oestrogen-receptor modulators Nat Rev Cancer 2007;7(1):46–53.PubMedCrossRefGoogle Scholar
  50. 50.
    Kuiper GG, Carlsson B, Grandien K et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997; 138(3):863–870.PubMedCrossRefGoogle Scholar
  51. 51.
    Monroe DG, Secreto FJ, Subramaniam M et al. Estrogen receptor alpha and beta heterodimers exert unique effects on estrogen-and tamoxifen-dependent gene expression in human U2OS osteosarcoma cells. Mol Endocrinol 2005; 19(6):1555–1568.PubMedCrossRefGoogle Scholar
  52. 52.
    Matthews J, Wihlen B, Tujague M et al. Estrogen receptor (ER) beta modulates ERalpha-mediated transcriptional activation by altering the recruitment of c-Fos and c-Jun to estrogen-responsive promoters. Mol Endocrinol 2006; 20(3):534–543.PubMedCrossRefGoogle Scholar
  53. 53.
    Tsai MJ, O’Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 1994; 63:451–486.PubMedCrossRefGoogle Scholar
  54. 54.
    Brzozowski AM, Pike AC, Dauter Z et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997; 389(6652):753–758.PubMedCrossRefGoogle Scholar
  55. 55.
    Pike AC, Brzozowski AM, Hubbard RE et al. Structure of the ligand-binding, domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 1999; 18(17):4608–4618.PubMedCrossRefGoogle Scholar
  56. 56.
    Liu H, Park WC, Bentrem DJ et al. Structure function relationships of the raloxifene-estrogen receptor-alpha complex for regulating transforming growth factor-alpha expression in breast cancer cells. J Biol Chem 2002; 277(11):9189–9198.PubMedCrossRefGoogle Scholar
  57. 57.
    MacGregor Schafer J, Liu H, Bentrem DJ et al. Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex is induced by substituting glycine for aspartate at amino acid 351. Cancer Res 2000; 60(18):5097–5105.PubMedGoogle Scholar
  58. 58.
    Webb P, Nguyen P, Kushner PJ. Differential SERM effects on corepressor binding dictate ERalpha activity in vivo. J Biol Chem 2003; 278(9):6912–6920.PubMedCrossRefGoogle Scholar
  59. 59.
    Hall JM, McDonnell DP. The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 1999; 140(12):5566–5578.PubMedCrossRefGoogle Scholar
  60. 60.
    Hall JM, McDonnell DP, Korach KS. Allosteric regulation of estrogen receptor structure, function and coactivator recruitment by different estrogen response elements. Mol Endocrinol 2002; 16(3):469–486.PubMedCrossRefGoogle Scholar
  61. 61.
    Lonard DM, O’Malley BW. The expanding cosmos of nuclear receptor coactivators. Cell 2006; 125(3):411–414.PubMedCrossRefGoogle Scholar
  62. 62.
    Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science 2002; 295(5564):2465–2468.PubMedCrossRefGoogle Scholar
  63. 63.
    Gottardis MM, Robinson SP, Satyaswaroop PG et al. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 1988; 48(4):812–815.PubMedGoogle Scholar
  64. 64.
    Lonard DM, Tsai SY, O’Malley BW. Selective estrogen receptor modulators 4-hydroxytamoxifen and raloxifene impact the stability and function of SRC-1 and SRC-3 coactivator proteins. Mol Cell Biol 2004; 24(1):14–24.PubMedCrossRefGoogle Scholar
  65. 65.
    Wu RC, Smith CL, O’Malley BW. Transcriptional regulation by steroid receptor coactivator phosphorylation. Endocr Rev 2005; 26(3):393–399.PubMedCrossRefGoogle Scholar
  66. 66.
    Smith CL, O’Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004; 25(1):45–71.PubMedCrossRefGoogle Scholar
  67. 67.
    McKenna NJ, Lanz RB, O’Malley BW. Nuclear receptor coregulators: cellular and molecular, biology. Endocr Rev 1999; 20(3):321–344.PubMedCrossRefGoogle Scholar
  68. 68.
    Shang Y, Hu X, DiRenzo J et al. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 2000; 103(6):843–852.PubMedCrossRefGoogle Scholar
  69. 69.
    Smith CL, Nawaz Z, O’Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 1997; 11(6):657–666.PubMedCrossRefGoogle Scholar
  70. 70.
    Lavinsky RM, Jepsen K, Heinzel T et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci USA 1998; 95(6):2920–2925.PubMedCrossRefGoogle Scholar
  71. 71.
    Jepsen K, Hermanson O, Onami TM et al. Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 2000; 102(6):753–763.PubMedCrossRefGoogle Scholar
  72. 72.
    Keeton EK, Brown M. Cell cycle progression stimulated by tamoxifen-bound estrogen receptor-alpha and promoter-specific effects in breast cancer cells deficient in N-CoR and SMRT. Mol Endocrinol 2005; 19(6):1543–1554.PubMedCrossRefGoogle Scholar
  73. 73.
    Mazumdar A, Wang RA, Mishra SK et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol 2001; 3(1):30–37.PubMedCrossRefGoogle Scholar
  74. 74.
    Montano MM, Ekena K, Delage-Mourroux R et al. An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proc Natl Acad Sci USA 1999; 96(12):6947–6952.PubMedCrossRefGoogle Scholar
  75. 75.
    Delage-Mourroux R, Martini PG, Choi I et al. Analysis of estrogen receptor interaction with a repressor of estrogen receptor activity (REA) and the regulation of estrogen receptor transcriptional activity by REA. J Biol Chem 2000; 275(46):35848–35856.PubMedCrossRefGoogle Scholar
  76. 76.
    Zhang J, Guenther MG, Carthew RW et al. Proteasomal regulation of nuclear receptor corepressor-mediated repression. Genes Dev 1998; 12(12):1775–1780.PubMedCrossRefGoogle Scholar
  77. 77.
    Frasor J, Danes JM, Funk CC et al. Estrogen down-regulation of the corepressor N-CoR: mechanism and implications for estrogen derepression of N-CoR-regulated genes. Proc Natl Acad Sci USA 2005; 102(37):13153–13157.PubMedCrossRefGoogle Scholar
  78. 78.
    Spencer TE, Jenster G, Burcin MM et al. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 1997; 389(6647):194–198.PubMedCrossRefGoogle Scholar
  79. 79.
    Liu XF, Bagchi MK. Recruitment of distinct chromatin-modifying complexes by tamoxifen-complexed estrogen receptor at natural target gene promoters in vivo. J Biol Chem 2004; 279(15):15050–15058.PubMedCrossRefGoogle Scholar
  80. 80.
    Feng Q, Yi P, Wong J et al. Signaling within a coactivator complex: methylation of SRC-3/AIB1 is a molecular switch for complex disassembly. Mol Cell Biol 2006; 26(21):7846–7857.PubMedCrossRefGoogle Scholar
  81. 81.
    Jordan VC. Selective estrogen receptor modulation: concept and consequences in cancer. Cancer Cell 2004; 5(3):207–213.PubMedCrossRefGoogle Scholar
  82. 82.
    Benz CC, Scott GK, Sarup JC et al. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 1992; 24(2):85–95.PubMedCrossRefGoogle Scholar
  83. 83.
    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(18):5183–5187.PubMedGoogle Scholar
  84. 84.
    Howell A, Robertson JF, Quaresma Albano J et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002 20(16):3396–3403.PubMedCrossRefGoogle Scholar
  85. 85.
    O’Regan RM, Osipo C, Ariazi E et al. Development and therapeutic options for the treatment of raloxifene-stimulated breast cancer in athymic mice. Clin Cancer Res 2006;12(7 Pt 1):2255–2263.PubMedCrossRefGoogle Scholar
  86. 86.
    Konecny G, Pauletti G, Pegram M et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003; 95(2):142–153.PubMedCrossRefGoogle Scholar
  87. 87.
    Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235(4785):177–182.PubMedCrossRefGoogle Scholar
  88. 88.
    Yu D, Hung MC. Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 2000; 19(53):6115–6121.PubMedCrossRefGoogle Scholar
  89. 89.
    Kurokawa H, Lenferink AE, Simpson JF et al. Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 2000; 60(20):5887–5894.PubMedGoogle Scholar
  90. 90.
    Shou J, Massarweh S, Osborne CK et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004; 96(12):926–935.PubMedCrossRefGoogle Scholar
  91. 91.
    Mc Ilroy M, Fleming FJ, Buggy Y et al. Tamoxifen-induced ER-alpha-SRC-3 interaction in HER2 positive human breast cancer; a possible mechanism for ER isoform specific recurrence. Endocr Relat Cancer 2006; 13(4):1135–1145.PubMedCrossRefGoogle Scholar
  92. 92.
    Schiff R, Massarweh SA, Shou J et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res 2004; 10(1 Pt 2):331S–336S.PubMedCrossRefGoogle Scholar
  93. 93.
    Tokunaga E, Kataoka A, Kimura Y et al. The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 2006; 42(5):629–635.PubMedCrossRefGoogle Scholar
  94. 94.
    Kirkegaard T, Witton CJ, McGlynn LM et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 2005; 207(2):139–146.PubMedCrossRefGoogle Scholar
  95. 95.
    Stoica GE, Franke TF, Wellstein A et al. Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Mol Endocrinol 2003; 17(5):818–830.PubMedCrossRefGoogle Scholar
  96. 96.
    Campbell RA, Bhat-Nakshatri P, Patel NM et al. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 2001; 276(13):9817–9824.PubMedCrossRefGoogle Scholar
  97. 97.
    Bunone G, Briand PA, Miksicek RJ et al. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 1996; 15(9):2174–2183.PubMedGoogle Scholar
  98. 98.
    Kato S, Endoh H, Masuhiro Y et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 1995; 270(5241):1491–1494.PubMedCrossRefGoogle Scholar
  99. 99.
    Osborne CK, Bardou V, Hopp TA et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 2003; 95(5):353–361.PubMedCrossRefGoogle Scholar
  100. 100.
    Likhite VS, Stossi F, Kim K et al. Kinase-specific phosphorylation of the estrogen receptor changes receptor interactions with ligand, deoxyribonucleic acid and coregulators associated with alterations in estrogen and tamoxifen activity. Mol Endocrinol 2006; 20(12):3120–3132.PubMedCrossRefGoogle Scholar
  101. 101.
    Knowlden JM, Hutcheson IR, Jones HE et al. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 2003; 144(3):1032–1044.PubMedCrossRefGoogle Scholar
  102. 102.
    Tsutsui S, Ohno S, Murakami S et al. Prognostic value of epidermal growth factor receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast cancer. Breast Cancer Res Treat 2002; 71(1):67–75.PubMedCrossRefGoogle Scholar
  103. 103.
    Fan P, Wang J, Santen RJ et al. Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res 2007; 67(3):1352–1360.PubMedCrossRefGoogle Scholar
  104. 104.
    Yang Z, Barnes CJ, Kumar R. Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells. Clin Cancer Res 2004; 10(11):3621–3628.PubMedCrossRefGoogle Scholar
  105. 105.
    Altomare DA, Testa JR. Perturbation of the AKT signaling pathway in human cancer. Oncogene 2005; 24(50):7455–7464.PubMedCrossRefGoogle Scholar
  106. 106.
    Ma L, Chen Z, Erdjument-Bromage H et al. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005; 121(2):179–193.PubMedCrossRefGoogle Scholar
  107. 107.
    Chang SB, Miron P, Miron A et al. Rapamycin inhibits proliferation of estrogen-receptor-positive breast cancer cells. J Surg Res 2007; 138(1):37–44.PubMedCrossRefGoogle Scholar
  108. 108.
    Yue W, Wang J, Li Y et al. Farnesylthiosalicylic acid blocks mammalian target of rapamycin signaling in breast cancer cells. Int J Cancer 2005; 117(5):746–754.PubMedCrossRefGoogle Scholar
  109. 109.
    deGraffenried LA, Friedrichs WE, Russell DH et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 2004; 10(23):8059–8067.PubMedCrossRefGoogle Scholar
  110. 110.
    Chu I, Sun J, Arnaout A et al. p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell 2007; 128(2):281–294.PubMedCrossRefGoogle Scholar
  111. 111.
    Wang LH, Yang XY, Zhang X et al. Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer. Cancer Cell 2006; 10(6):487–499.PubMedCrossRefGoogle Scholar
  112. 112.
    Arpino G, Gutierrez C, Weiss H et al. Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst 2007; 99(9):694–705.PubMedCrossRefGoogle Scholar
  113. 113.
    Osipo C, Meeke K, Liu H et al. Trastuzumab therapy for tamoxifen-stimulated endometrial cancer. Cancer Res 2005; 65(18):8504–8513.PubMedCrossRefGoogle Scholar
  114. 114.
    Johnston SR. Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer. Clin Cancer Res 2006; 12(3 Pt 2):1061s–1068s.PubMedCrossRefGoogle Scholar
  115. 115.
    Massarweh S, Osborne CK, Jiang S et al. Mechanisms of Tumor Regression and Resistance to Estrogen Deprivation and Fulvestrant in a Model of Estrogen Receptor-Positive, HER-2/neu-Positive Breast Cancer. Cancer Res 2006; 66(16):8266–8273.PubMedCrossRefGoogle Scholar
  116. 116.
    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.PubMedGoogle Scholar
  117. 117.
    Yao K, Lee ES, Bentrem DJ et al. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 2000; 6(5):2028–2036.PubMedGoogle Scholar
  118. 118.
    Liu H, Lee ES, Gajdos C et al. Apoptotic action of 17beta-estradiol in raloxifene-resistant MCF-7 cells in vitro and in vivo. J Natl Cancer Inst 2003; 95(21):1586–1597.PubMedGoogle Scholar
  119. 119.
    O’Regan RM, Gajdos C, Dardes RC et al. Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice J Natl Cancer Inst 2002; 94(4):274–283.PubMedGoogle Scholar
  120. 120.
    Haddow A, Watkinson J, Paterson E. Influence of synthetic oestrogens upon advanced malignant disease. Br Med J 1944; 2:393–398.CrossRefPubMedGoogle Scholar
  121. 121.
    Lonning PE, Taylor PD, Anker G et al. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat 2001; 67(2):111–116.PubMedCrossRefGoogle Scholar
  122. 122.
    Song RX, Mor G, Naftolin F et al. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 2001; 93(22):1714–1723.PubMedCrossRefGoogle Scholar
  123. 123.
    Lewis JS, Osipo C, Meeke K et al. Estrogen-induced apoptosis in a breast cancer model resistant to long-term estrogen withdrawal. J Steroid Biochem Mol Biol 2005;94(1–3):131–141.PubMedCrossRefGoogle Scholar
  124. 124.
    Lewis JS, Meeke K, Osipo C et al. Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation. J Natl Cancer Inst 2005; 97(23):1746–1759.PubMedCrossRefGoogle Scholar
  125. 125.
    Jordan VC, Lewis JS, Osipo C et al. The apoptotic action of estrogen following exhaustive antihormonal therapy: a new clinical treatment strategy. Breast 2005; 14(6):624–630.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  1. 1.Alfred G. Knudson Chair of Cancer ResearchFox Chase Cancer CenterPhiladelphiaUSA

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