Role of Altered Estrogen Receptors in Breast Cancer

  • Sami G. Diab
  • Carl G. Castles
  • Suzanne A. W. Fuqua
Part of the Hormones in Health and Disease book series (HHD)


Breast cancer is the most common malignancy in women in the United States, and is predicted to account for about 32% of new cancer cases in 1995 (Wingo et al., 1995). One of the first pieces of evidence to suggest that breast tumors depend on estrogen for growth comes from the observation, made more than a century ago, that oophorectomy can cause tumor shrinkage in women with metastatic breast cancer (Beatson, 1896). The discovery of the estrogen receptor (ER) as a mediator of estrogen’s biological effects revolutionized our understanding of breast cancer biology and eventually led to the classification of breast cancer into two major groups: those tumors that express the ER (ER-positive), and those tumors with undetectable levels of the ER (ER-negative). We now appreciate that each of these groups has its own distinct biological and clinical features.


Breast Cancer Estrogen Receptor Atypical Ductal Hyperplasia Estrogen Receptor Gene Estrogen Receptor mRNA 
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.


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  1. Allred DC (1993): Should immunohistochemieal examination replace biochemical hormone receptor assays in breast cancer? Am J Clin Pathol 99: 1 - 3PubMedGoogle Scholar
  2. Allred DC, O’Connell P, Fuqua SA, Osborne CK (1994): Immunohistochemicalstudies of early breast cancer evolution. Breast Cancer Res Treat 32: 13–18PubMedCrossRefGoogle Scholar
  3. Andersen J, Poulsen HS (1989): Immunohistochemical estrogen receptor determination in paraffin-embedded tissue. Prediction of response to hormonal treatment in advanced breast cancer. Cancer 64: 1901–1908PubMedCrossRefGoogle Scholar
  4. Arrick BA, Korc M, Derynck R (1990): Differential regulation of expression of three transforming growth factor (3 species in human breast cancer cell lines by estradiol. Cancer Res 50: 299–303PubMedGoogle Scholar
  5. Balaguer P, Demirpence E, Pons M, Gagne D, Bocquel MT, Gronemeyer H, Nicolas JC (1991): Retinoic acid has an antiestrogenic effect on different regulated estrogen genes in different cellular types. C R Seances Soc Biol Fil 185: 434–443PubMedGoogle Scholar
  6. Beatson GT (1896): On the treatment of inoperable cases of carcinogen of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 2: 104–107, 162–167Google Scholar
  7. Bobrow LG, Happerfield LC, Gregory WM, Springall RD, Millis RR (1994): The classification of ductal carcinoma in situ and its association with biological markers. Semin Diagn Pathol 11: 199–207PubMedGoogle Scholar
  8. Castles CG, Fuqua SAW, Klotz DM, Hill SM (1993): Expression of a constitutively active estrogen receptor variant in the estrogen receptor-negative BT-20 human breast cancer cell line. Cancer Res 53: 5934–5939PubMedGoogle Scholar
  9. Cavailles V, Dauvois S, Danielian PS, Parker MG (1994): Interaction of proteins with transcriptionally active estrogen receptors. Proc Natl Acad Sci USA 91: 10009–10013PubMedCrossRefGoogle Scholar
  10. Chambraud B, Berry M, Redeuilh G, Chambon P, and Balieu EE (1990): Several regions of human estrogen receptor are involved in the formation of receptor- heat shock protein 90 complexes. J Biol Chem 265: 20686–20691PubMedGoogle Scholar
  11. Chrysogelos SA, Dickson RB (1994): EGF receptor expression, regulation, and function in breast cancer. Breast Cancer Res Treat 29: 29–40PubMedCrossRefGoogle Scholar
  12. Clark GM, Osborne CK, McGuire WL (1984): Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J Clin Oncol 2: 1102–1109PubMedGoogle Scholar
  13. Daffada AA, Johnston SR, Smith IE, Detre S, King N, Dowsett M (1995): Exon 5 deletion variant estrogen receptor messenger RNA expression in relation to tamoxifen resistance and progesterone receptor/pS2 status in human breast cancer. Cancer Res 55: 288–293PubMedGoogle Scholar
  14. Dana SL, Hoener PA, Wheeler DA, Lawrence CB, McDonnell DP (1994): Novel estrogen response elements identified by genetic selection in yeast are differentially responsive to estrogens and antiestrogens in mammalian cells. Mol Endocrinol 8: 1193–1207PubMedCrossRefGoogle Scholar
  15. Danielian PS, White R, Lees JA, Parker MG (1992): Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J 11: 1025–1033PubMedGoogle Scholar
  16. Danielian PS, White, R, Hoare SA, Fawell SE, Parker MG (1993): Identification of residues in the estrogen receptor that confer differential sensitivity to estrogen and hydroxytamoxifen. Mol Endocrinol 7: 232–240PubMedCrossRefGoogle Scholar
  17. Davidoff AM, Kerns BJ, Iglehart JD, Marks JR (1991): Maintenance of p53 altera¬tions throughout breast cancer progression. Cancer Res 51: 2605–2610PubMedGoogle Scholar
  18. DeFriend DJ, Blarney RE, Robertson JF, Walton P, Howell, A (1993): Response to the pure antiestrogen ICI 182780 after tamoxifen failure in advanced breast cancer: 16th annual San Antonio breast cancer symposium (abstract). Breast Cancer Res Treat 27: 136Google Scholar
  19. Evans RM (1988): The steroid and thyroid hormone receptor superfamily. Science 240: 889 - 895PubMedCrossRefGoogle Scholar
  20. Fawell SE, Lees J A, White R, Parker MG (1990): Characterization and co-localization of steroid binding and dimerization activities in the mouse estrogen receptor. Cell 60: 953–962PubMedCrossRefGoogle Scholar
  21. Fearon ER and Vogelstein B (1990): A genetic model for colorectal tumorigenesis. Cell 61: 759–767PubMedCrossRefGoogle Scholar
  22. Ferguson AT, Lapidus RG, Davidson NE (1995): Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer can reactivate estrogen receptor gene expression. In Proceedings of 86th Ann Meeting of Am Assoc Cancer Res, Toronto, Canada, 269.Google Scholar
  23. Fuqua SAW, Fitzgerald SD, McGuire WL (1990): A simple polymerase chain reaction method for detection and cloning of low-abundance transcripts. Bio- Techniques 9: 206–211Google Scholar
  24. Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O’Malley BW, McGuire WL (1991): Variant human breast tumor estrogen receptor with constitutive transcriptional activity. Cancer Res 51: 105–109PubMedGoogle Scholar
  25. Fuqua SAW, Fitzgerald SD, Allred DC, Elledge RM, Nawaz Z, McDonnell DP, O’Malley BW, Greene GL, McGuire WL (1992): Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors. Cancer Res 52: 483–486PubMedGoogle Scholar
  26. Fuqua SAW, Allred DC, Elledge RM, Krieg SL, Benedix MG, Nawaz Z, O’MalleyBW, Greene GL, McGuire WL (1993): The ER-positive/PgR-negative breast cancer phenotype is not associated with mutations within the DNA binding domain. Breast Cancer Res Treat 26: 191–202PubMedCrossRefGoogle Scholar
  27. Fuqua SAW, Wiltschke, C, Castles C, Wolf D, and Allred DC (1995): A role for estrogen-receptor variants in endocrine resistance. Endocrine-Related Cancer 2: 19–25CrossRefGoogle Scholar
  28. Gosden JR, Middleton PG, Rout D (1986): Localization of the human oestrogen receptor gene to the chromosome 6q24 q27 by in situ hybridization. Cytogenet Cell Genet 43: 218–220PubMedCrossRefGoogle Scholar
  29. Greene GL, Sobel N, King WJ, Jensen EJ (1984): Immunochemical studies of estrogen receptors. J Steroid Biochem 20: 51–56PubMedCrossRefGoogle Scholar
  30. Guiochon-Mantel A, Loosfelt H, Lescop P, Sar S, Atger M, Perrot-Applanat M, Milgrom, E (1989): Mechanisms of nuclear localization of the progesterone receptor: evidence for interaction between monomers. I 57: 1147–1154Google Scholar
  31. Gusterson BA, Machin LG, Gullick WJ, Gibbs NM, Powles TJ, Elliott C, Ashley S, Monaghan P, Harrison, S (1988): c-erb-B2 expression in benign and malignant breast disease. Br J Cancer 58: 453 - 457Google Scholar
  32. Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown, M (1994): Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. Science 264: 1455–1458PubMedCrossRefGoogle Scholar
  33. Harlow KW, Smith DN, Katzenellenbogen JA, Green GL, Katzenellenbogen BS (1989): Identification of cysteine 530 as the covalent attachment site of an affinity-labeling estrogen (ketononestrol aziridine) and antiestrogen (tamoxifen aziridine) in the human estrogen receptor. J Biol Chem 164: 17476–17485Google Scholar
  34. Hill SM, Fuqua SAW, Chamness GC, Greene GL, McGuire WL (1989): Estrogen receptor expression in human breast cancer associated with an estrogen receptor gene restriction fragment length polymorphism. Cancer Res 49: 145–148PubMedGoogle Scholar
  35. Horwitz KB, McGuire WL (1978): Estrogen control of progesterone receptor in human breast cancer. J Biol Chem 253: 2223–2228PubMedGoogle Scholar
  36. Horwitz KB, McGuire WL, Pearson OH, Segaloff A (1975): Predicting response to endocrine therapy in human breast cancer: a hypothesis. Science 189: 726–727PubMedCrossRefGoogle Scholar
  37. Horwitz KB, Wei LL, Sedlacek SM, D’Arville CN (1985): Progestin action and progesterone receptor structure in human breast cancer: a review. Rec Prog Horm Res 41: 249–316PubMedGoogle Scholar
  38. Ignar-Trowbridge DM, Teng CT, Ross KA, Parker MG, Korach KS, McLachlan JA (1993): Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element. Mol Endocrinol 7: 992–998PubMedCrossRefGoogle Scholar
  39. Jacquemier JD, Rolland PH, Vague D, Lieutaud R, Spitalier JM, Martin PM (1982): Relationships between steroid receptor and epithelial cell proliferation in benign fibrocystic disease of the breast. Cancer 49: 2534–2536PubMedCrossRefGoogle Scholar
  40. Jacquemier JD, Hassoun J, Torrente M, Martin PM (1990): Distribution of estrogen and progesterone receptors in healthy tissue adjacent to breast lesions at various stages immunohistochemical study of 107 cases. Breast Cancer Res Treat 15: 109–117PubMedCrossRefGoogle Scholar
  41. Jiang S-Y, Jordan VC (1992): Growth regulation of estrogen receptor-negative breast cancer cells transfected with complementary DNAs for estrogen receptor. J Natl Cancer Inst 84: 580–591PubMedCrossRefGoogle Scholar
  42. Jiang S-Y, Langan-Fahey SM, Stella AL, McCague R, Jordan VC (1992): Point mutation of estrogen receptor (ER) in the ligand binding domain changes the pharmacology of antiestrogens in ER-negative breast cancer cells stably expressing cDNA’s for ER. Mol Endocrinol 6: 2167–2174PubMedCrossRefGoogle Scholar
  43. Keaveney M, Klug J, Dawson M, Nestor PV, Neilan JG, Forde RC, Gannon F (1991): Evidence of a previously unidentified upstream exon in the human oestro-gen receptor gene. J Molec Endocrinol 6: 111–115CrossRefGoogle Scholar
  44. Khan SA, Rogers MA, Obando JA, Tamsen A (1994): Estrogen receptor expression of benign breast epithelium and its association with breast cancer. Cancer Res 54: 993–997PubMedGoogle Scholar
  45. Klein-Hitpass L, Schorpp M, Wagner U, Ryffel GU (1986): An estrogen-responsive element derived from the 5′ flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells. Cell 46: 1053–1061PubMedCrossRefGoogle Scholar
  46. Klotz DK, Castles CG, Hill SM (1993): Variant ER mRNAs are expressed in the MDA-MB-330 and other human breast tumor cell lines. In Proceedings of 75th Annual Meeting Endocrine Society, Las Vegas NV, 515.Google Scholar
  47. Knight WAI, Livingston RB, Gregory EJ, McGuire WL (1977): Estrogen receptor is an independent prognostic factor for early recurrence in breast cancer. Cancer Res 37: 4669–4671PubMedGoogle Scholar
  48. Kumar V, Chambon P (1988): The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer. Cell 55: 145–156PubMedCrossRefGoogle Scholar
  49. Kumar V, Green S, Stack G, Berry M, Jin J, Chambon, P (1987): Functional domains of the human estrogen receptor. Cell 51: 941–951PubMedCrossRefGoogle Scholar
  50. Kushner PJ, Hort E, Shine J, Baxter JD, Greene GL (1990): Construction of cell lines that express high levels of the human estrogen receptor and are killed by estrogens. Mol Endocrinol 4: 1465–1473PubMedCrossRefGoogle Scholar
  51. Matsui Y, Halter SA, Holt JT, Hogan BL, Coffey RJ (1990): Development of mammary hyperplasia and neoplasia in MMTV-TGFa transgenic mice. Cell 61: 1147–1155PubMedCrossRefGoogle Scholar
  52. McDonnell DP, Vegeto E, O’Malley BW (1992): Identification of a negative regulatory function for steroid receptors. Proc Natl Acad Sci USA 89: 10563–10567PubMedCrossRefGoogle Scholar
  53. McGuire WL (1978): Hormone receptors: their role in predicting prognosis and response to endocrine therapy. Semin Oncol 5: 428–433PubMedGoogle Scholar
  54. McGuire WL, Carbone PP, Vollmer EP (1975): Estrogen Receptors in Human Breast Cancer. New York: Raven PressGoogle Scholar
  55. Meirik O, Lund E, Adami H (1986): Oral contraceptives and breast cancer in young women. Lancet 2: 650–653PubMedCrossRefGoogle Scholar
  56. Metzger D, White JH, Chambon, P (1988): The human oestrogen receptor functions in yeast. Nature 334: 31–36PubMedCrossRefGoogle Scholar
  57. Murphy LC, Dotzlaw, H (1989): Regulation of transforming growth factor a and transforming growth factor (3 messenger ribonucleic acid abundance in T-47D, human breast cancer cells. Mol Endocrinol 3: 611–617PubMedCrossRefGoogle Scholar
  58. O’Connell P, Pekkel V, Fuqua S, Osborne CK, Allred DC (1994): Molecular genetic studies of early breast cancer evolution. Breast Cancer Res Treat 32: 5–12PubMedCrossRefGoogle Scholar
  59. Osborne CK, Yochmowitz MG, Knight WA, McGuire WL (1980): The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 46: 2884–2888Google Scholar
  60. Ottaviano YL, Issa JP, Pari FF, Smith HS, Baylin SB, Davidson NE (1994): Methy lation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res 54: 2552–2555PubMedGoogle Scholar
  61. Pakdel F, Katzenellenbogen BS (1992): Human estrogen receptor mutants with altered estrogen and antiestrogen ligand discrimination. J Biol Chem 267: 3429–3437PubMedGoogle Scholar
  62. Petersen OW, Hoyer PE, van Deurs, B (1987): Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue. Cancer Res 47: 5748–5751PubMedGoogle Scholar
  63. Petrangeli E, Lubrano C, Ortolani F, Ravenna L, Vacca A, Sciacchitano S, Frati L, Gulino, A (1994): Estrogen receptors: new perspectives in breast cancer management. J Steroid Biochem Mol Biol 49: 327–331PubMedCrossRefGoogle Scholar
  64. Pierrat B, Heery DM, Chambon P, Losson, R (1994): A highly conserved region in the hormone-binding domain of the human estrogen receptor functions as an efficient transactivation domain in yeast. Gene 143: 193–200PubMedCrossRefGoogle Scholar
  65. Piva R, Bianchini E, Kumar YL, Chambon P, Del Senno, L (1988): Estrogen induced increase of estrogen receptor RNA in human breast cancer cells. Biochem Biophys Res Commun 155:943–949 PollerGoogle Scholar
  66. DN, Roberts EC, Bell JA, Elston CW, Blarney RW, Ellis IO (1993a): p53 protein expression in mammary ductal carcinoma in situ: relationship to immunohistochemical expression of estrogen receptor and c-erbB-2 protein. Hum Pathol 24: 463–468Google Scholar
  67. Poller DN, Snead DRJ, Roberts EC, Galea M, Bell JA, Gilmour A, Elston CW, Blarney RW, Ellis IO (1993b): Oestrogen receptor expression in ductal carcinoma in-situ of the breast: relationship to flow cytometric analysis of DNA and expression of the c-erb-2 oncoprotein. Br J Cancer 68: 156–161PubMedCrossRefGoogle Scholar
  68. Ratajczak T, Wilkinson SP, Brockway MJ, Hahnel R, Moritz RL, Begg GS, Simpson RJ (1989): The interaction site for tamoxifen aziridine with the bovine estrogen receptor. J Biol Chem 264: 13453–13459PubMedGoogle Scholar
  69. Ravdin PM, Green S, Dorr TM, McGuire WL, Fabian C, Pugh RP, Carter RD, Rivkin SE, Borst JR, Belt RJ, Metch B, Osborne CK (1992): Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study. J Clin Oncol 10: 1284–1291PubMedGoogle Scholar
  70. Ricketts D, Turnbull L, Ryall G, Bakhshi R, Rawson NSB, Gazet J-C, Nolan C, Coombes RC (1991): Estrogen and progesterone receptors in the normal female breast. Cancer Res 51: 1817–1822PubMedGoogle Scholar
  71. Roman SD, Clarke CL, Hall RE, Alexander IE, Sutherland RL (1992): Expression and regulation of retinoic acid receptors in human breast cancer cells. Cancer Res 52: 2236–2242PubMedGoogle Scholar
  72. Roodi N, Bailey LR, Kao WY, Verrier CS, Yee CJ, Dupont WD, Pari FF (1995): Estrogen receptor gene analysis in estrogen receptor-positive and receptor- negative primary breast cancer. J Natl Cancer Inst 87: 446–451PubMedCrossRefGoogle Scholar
  73. Smith HS, Lu Y, Deng G, Martinez O, Krams S, Ljung BM, Thor A, Lagios M (1993): Molecular aspects of early stages of breast cancer progression. J Cell Biochem Suppl 17G: 144–152CrossRefGoogle Scholar
  74. Stewart JF, King, R JB, Sexton SA, Millis RR, Rubens RD, Hayward JL (1981): Oestrogen receptors, sites of metastatic disease and survival in recurrent breast cancer. Eur J Cancer 17: 449–453PubMedGoogle Scholar
  75. Tasset D, Tora L, Fromental C, Scheer E, Chambon, P (1990): Distinct classes of transcriptional activating domains function by different mechanisms. Cell 62: 1177–1178PubMedCrossRefGoogle Scholar
  76. Tesch M, Shawwa A, Henderson, R (1993): Immunohistochemical determination of estrogen and progesterone receptor status in breast cancer. Am J Clin Pathol 99: 8–12PubMedGoogle Scholar
  77. Trichopoulos D, MacNahon B, Cole, P (1972): Menopause and breast cancer risk. J Natl Cancer Inst 48: 605–613PubMedGoogle Scholar
  78. Tsutsumi Y, Naber SP, DeLellis RA, Wolfe HJ, Marks PJ, McKenzie SJ, Yin S (1990): neu oncogene protein and epidermal growth factor receptor are independently expressed in benign and malignant breast tissues. Hum pathol 21: 750–758.Google Scholar
  79. Tzukerman MT, Esty A, Santisomere D, Danielian P, Parker MG, Stein RB, Pike JW, McDonnell DP (1994): Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 8: 21–30PubMedCrossRefGoogle Scholar
  80. Wakeling AE (1993): Are breast tumours resistant to tamoxifen also resistant to pure antiestrogens J Steroid Biochem Molec Biol 47: 107–114PubMedCrossRefGoogle Scholar
  81. Wang Y, Miksicek RJ (1991): Identification of a dominant negative form of the human estrogen receptor. Mol Endocrinol 5: 1707–1715PubMedCrossRefGoogle Scholar
  82. Watts CKW, Parker MG, King RJB (1989): Stable transfection of the oestrogen receptor gene into a human osteosarcoma cell line. J Steroid Biochem 34: 483–490PubMedCrossRefGoogle Scholar
  83. Webster NJG, Green S, Jin J-R, Chambon, P (1988): The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function. Cell 54: 199–207PubMedCrossRefGoogle Scholar
  84. Webster NJG, Green S, Tasset D, Ponglikitmongkol M, Chambon, P (1989): The transcription activation function located in the hormone-binding domain of the human oestrogen receptor is not encoded by a single exon. EMBO J 8: 1441–1446Google Scholar
  85. Weigel RJ, deConinck EC (1993): Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma. Cancer Res 53: 3472–3474PubMedGoogle Scholar
  86. Wingo PA, Tong T, Bolden S (1995): Cancer Statistics, 1995. CA 45: 8–31Google Scholar
  87. Yaich LE, Dupont WD, Cavener DR, Pari FF (1992): Analysis of the PvuII restriction fragment polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. Cancer Res 52: 77–83PubMedGoogle Scholar
  88. Zhang, Q-X, Borg A, Fuqua SAW (1993): An exon 5 deletion variant of the estrogen receptor frequently coexpressed with wild-type estrogen receptor in human breast cancer. Cancer Res 53: 5882–5884PubMedGoogle Scholar

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© Birkhäuser Boston 1996

Authors and Affiliations

  • Sami G. Diab
  • Carl G. Castles
  • Suzanne A. W. Fuqua

There are no affiliations available

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