Breast Cancer Research and Treatment

, Volume 51, Issue 3, pp 227–238

Steroid hormone receptors in breast cancer management

  • C. Kent Osborne
Article

Abstract

Estrogen and progesterone receptors (ER and PR) have now been studied in clinical breast cancer for more than 20 years. Positive receptor status correlates with favorable prognostic features including a lower rate of cell proliferation and histologic evidence of tumor differentiation. During the first several years after diagnosis, patients with ER-positive tumors tend to have a lower recurrence rate; however, this is balanced by a higher recurrence rate in subsequent years so that the overall prognostic significance of receptor status is modest. ER and PR have their greatest utility in predicting response to hormonal therapy, both in the adjuvant setting and for advanced disease. When the assay is done properly and cut-offs for ER-negativity and positivity are defined by clinical studies of patients treated with endocrine therapy, receptor status is very helpful in identifying groups of patients who are very unlikely to benefit from hormonal therapy. Tumors that express both ER and PR have the greatest benefit from hormonal therapy, but those containing only ER or only PR still have significant responses.

Two types of estrogen receptors, ERα and ERβ, have now been identified. Although there is considerable homology between these receptor forms, they appear to have important structural and functional differences that may be important for tissue and promoter- specific regulation of gene expression. These receptor forms, as well as ER variants and mutants, may also contribute to hormonal sensitivity and resistance. PR also exists in two forms, PRA and PRB. PRA appears to have repressor functions on both PRB and ERα, and the ratio of PRA to PRB in clinical breast tumors needs to be studied for its possible clinical relevance. Expression of receptor- interacting proteins can also modulate ER transcriptional activity, and these too need additional study to determine if they are markers of hormonal sensitivity or resistance. In summary, ER and PR status are important biomarkers that help physicians individualize therapy.

breast cancer estrogen receptors progesterone receptors hormone therapy prognosis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Jensen EV, DeSombre ER: Mechanism of action of the female sex hormones. Annu Rev Biochem 41:203–230, 1972Google Scholar
  2. 2.
    Gorski J, Toft DO, Shyamala G, Smith D, Notides A: Hormone receptors: Studies on the interaction of estrogen with uterus. Recent Prog Horm Res 24:45–80, 1968Google Scholar
  3. 3.
    Osborne CK, Yochmowitz MG, Knight WA, McGuire WL: The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 46:2884–2888, 1980Google Scholar
  4. 4.
    Clark GM, Osborne CK, McGuire WL: Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J Clin Oncol 2:1102–1109, 1984Google Scholar
  5. 5.
    Glass GK, Rose DW, Rosenfeld MG: Nuclear receptor coactivators. Curr Opin Cell Biol 9:222–232, 1997Google Scholar
  6. 6.
    Osborne CK, Elledge RM, Fuqua SAW: Estrogen receptors in breast cancer therapy. Sci Med 3:32–41, 1996Google Scholar
  7. 7.
    Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L: Nuclear receptor coactivators and corepressors. Mol Endocrinol 10:1167–1177, 1996Google Scholar
  8. 8.
    Anzick AL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan X-Y, Sauter G, Kallioniemi O-P, Trent JM, Meltzer PS: AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277:965–968, 1997Google Scholar
  9. 9.
    Hörlein AJ, Näär AM, Helnzel T, Tochia J, Gloss B, Kurokawa R, Ryan A, Kamel Y, Söderström M, Glass CK, Rosenfeld MG: Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377:397–404, 1995Google Scholar
  10. 10.
    Li H, Leo C, Schroen DJ, Chen JD: Characterization of receptor interaction and transcriptional repression by the corepressor SMRT. Mol Endocrinol 11:2025–2037, 1997Google Scholar
  11. 11.
    Nagy L, Kao H-Y, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM: Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89:373–380, 1997Google Scholar
  12. 12.
    Jackson WA, Richer RK, Bain DL, Takimoto GS, Tung L, Horwitz KB: The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol Endocrinol 11:693–705, 1997Google Scholar
  13. 13.
    Smith CL, Nawaz Z, O'Malley BW: Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 11:657–666, 1997Google Scholar
  14. 14.
    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, 1994Google Scholar
  15. 15.
    Webb P, Lopez GN, Uht RM, Kushner PJ: Tamoxifen activation of the estrogen receptor/AP-1 pathway: Potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol 9:443–456, 1995Google Scholar
  16. 16.
    Kuiper GG, Enmark E, Pelto-Huikko P, Nilsson S, Gustafsson JA: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930, 1996Google Scholar
  17. 17.
    Mosselman S, Polman J, Dijkema R: ERß: identification and characterization of a novel human estrogen receptor. FEBS Lett 392:49–53, 1996Google Scholar
  18. 18.
    Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA: Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 138:863–870, 1997Google Scholar
  19. 19.
    Montano MM, Muller V, Trobaugh A, Katzenellenbogen BS: The carboxy-terminal F domain of the human estrogen receptor: role in the transcriptional activity of the receptor and the effectiveness of antiestrogens as estrogen antagonists. Mol Endocrinol 9:814–825, 1995Google Scholar
  20. 20.
    Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, Giguere V: Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor ß. Mol Endocrinol 11:353–365, 1997Google Scholar
  21. 21.
    Dotzlaw H, Leygue E, Watson PH, Murphy LC: Expression of estrogen receptor-beta in human breast tumors. J Clin Endocrinol Metab 82:2371–2374, 1997Google Scholar
  22. 22.
    Cowley SM, Hoare S, Mosselman S, Parker MG: Estrogen receptors α and β form heterodimers on DNA. J Biol Chem 272:19858–19862, 1997Google Scholar
  23. 23.
    Paech K, Webb P, Kuiper GGJM, Nilsson S, Gustafsson J-A, Kushner PJ, Scanlan TS: Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277:1508–1510, 1997Google Scholar
  24. 24.
    Osborne CK: Receptors. In: Harris J, Hellman S, Henderson IC, Kinne DW (eds) Breast Diseases, 2d Edition. JB Lippincott Co, Philadelphia PA, 1991, pp 301–325Google Scholar
  25. 25.
    Hull DF, Clark GM, Osborne CK, Chamness GC, Knight WA, McGuire WL: Multiple estrogen receptor assays in human breast cancer. Cancer Res 43:413–416, 1983Google Scholar
  26. 26.
    Green GL, Sobel NB, King WJ, Jensen EV: Immunochemical studies of estrogen receptors. J Steroid Biochem 20:51–56, 1984Google Scholar
  27. 27.
    King WJ, Green GL: Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature 307:745–747, 1984.Google Scholar
  28. 28.
    McGuire WL, Vollmer EP, Carbone PP (eds): Estrogen Receptors in Human Breast Cancer. Raven Press, New York, 1975Google Scholar
  29. 29.
    Allred DC, Bustamante MA, Daniel CO, Gaskill HV, Cruz ABJ: Immunocytochemical analysis of estrogen receptors in human breast carcinomas. Evaluation of 130 cases and review of the literature regarding concordance with biochemical assay and clinical relevance. Arch Surg 125:107–113, 1990Google Scholar
  30. 30.
    Millis RR: Correlation of hormone receptors with pathological features in human breast cancer. Cancer 46:2869–2871, 1980Google Scholar
  31. 31.
    Fisher ER, Osborne CK, McGuire WL, Redmond C, Knight WA, Fisher B, Bannayan G, Walder A, Jacobson AA, Queen DM, Bennett DE, Ford HC: Correlation of primary breast cancer histopathology and estrogen receptor content. Breast Cancer Res Treat 1:37–41, 1981Google Scholar
  32. 32.
    Maynard PV, Davies CJ, Blamey RW, Elston CW, Johnson J, Griffiths K: Relationship between oestrogen-receptor content and histological grade in human primary breast tumours. Br J Cancer 38:745–748, 1978Google Scholar
  33. 33.
    Fisher ER, Redmond CK, Liu H, Rockette H, Fisher B: Correlation of estrogen receptor and pathologic characteristics of invasive breast cancer. Cancer 45:349–353, 1980Google Scholar
  34. 34.
    Glaubitz LC, Bowen JH, Cox EB, McCarty KS: Elastosis in human breast cancer. Correlation with sex steroid receptors and comparison with clinical outcome. Arch Pathol Lab Med 108:27–30, 1984Google Scholar
  35. 35.
    Meyer JS, Rao BR, Stevens SC, White WL: Low incidence of estrogen receptor in breast carcinomas with rapid rates of cellular replication. Cancer 40:2290–2298, 1977Google Scholar
  36. 36.
    Wenger CR, Beardslee S, Owens MA, Pounds G, Oldaker T, Vendely P, Pandian MR, Harrington D, Clark GM, McGuire WL: DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients. Breast Cancer Res Treat 28:9–20, 1993Google Scholar
  37. 37.
    Walt AJ, Singhakowinta A, Brooks SC, Cortez A: The surgical implications of estrophile protein estimations in carcinoma of the breast. Surgery 80:506–512, 1976Google Scholar
  38. 38.
    Knight WA III, Livingston RB, Gregory EJ, McGuire WL: Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer. Cancer Res 37:4669–4671, 1977Google Scholar
  39. 39.
    Allegra JC, Lippman ME, Simon R, Thompson EB, Barlock A, Green L, Huff KK, Do HM, Aitken SC, Warren R: Association between steroid hormone receptor status and disease-free interval in breast cancer. Cancer Treat Rep 63:1271–1277, 1979Google Scholar
  40. 40.
    Westerberg H, Gustafson SA, Nordenskjold B, Silfversward C, Wallgren A: Estrogen receptor level and other factors in early recurrence of breast cancer. Int J Cancer 26:429–433, 1980Google Scholar
  41. 41.
    Bishop HM, Blamey RW, Elston CW, Haybittle JL, Nicholson RI, Griffiths K: Relationship of oestrogen-receptor status to survival in breast cancer. Lancet 2:283–284, 1979Google Scholar
  42. 42.
    Nicholson RI, Campbell FC, Blamey RW, Elston CW, George D, Griffiths K: Steroid receptors in early breast cancer: Value in prognosis. J Steroid Biochem 15:193–199, 1981Google Scholar
  43. 43.
    Crowe JP, Hubay CA, Pearson OH, Marshall JS, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, McGuire WL: Estrogen receptor status as a prognostic indicator for stage I breast cancer patients. Breast Cancer Res Treat 2:171–176, 1982Google Scholar
  44. 44.
    Aamdal S, Bormer O, Jorgensen O, Host H, Eliassen G, Kaalhus O, Pihl A: Estrogen receptors and long-term prognosis in breast cancer. Cancer 53:2525–2529, 1984Google Scholar
  45. 45.
    Hahnel R, Woodings T, Vivian AB: Prognostic value of estrogen receptors in primary breast cancer. Cancer 44:671–675, 1979Google Scholar
  46. 46.
    Hilsenbeck SG, Ravdin PM, de Moor C, Osborne CK, Clark GM: Paradoxical decreases in prognostic utility as datasets mature: Time-dependent lack of proportional hazards in prognostic factors in primary breast cancer. Breast Cancer Res Treat 37(suppl):35, 1996Google Scholar
  47. 47.
    Lippman ME, Allegra JC: Quantitative estrogen receptor analyses: The response to endocrine and cytotoxic chemotherapy in human breast cancer and the disease-free interval. Cancer 46:2829–2834, 1980Google Scholar
  48. 48.
    Paridaens R, Sylvester RJ, Ferrazzi E, Legros N, Leclercq G, Heuson JC: Clinical significance of the quantitative assessment of estrogen receptors in advanced breast cancer. Cancer 46:2889–2895, 1980Google Scholar
  49. 49.
    Campbell FC, Blamey RW, Elston CW, Morris AH, Nicholson RI, Griffiths K, Haybittle JL: Quantitative oestradiol receptor values in primary breast cancer and response of metastases to endocrine therapy. Lancet 2:1317–1319, 1981Google Scholar
  50. 50.
    Knight WA, Osborne CK, McGuire WL: Hormone receptors in primary and advanced breast cancer. Clin Endocrinol Metab 9:361–368, 1980Google Scholar
  51. 51.
    Osborne CK, Clark GM, Ravdin PM: Adjuvant systemic therapy of primary breast cancer. In: Harris JR, Lippman ME, Hellman S (eds) Diseases of the Breast. Lippincott-Raven Publishers, Philadelphia PA, 1996, pp 546–576Google Scholar
  52. 52.
    NATO Steering Committee: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Br J Cancer 57:608–611, 1988Google Scholar
  53. 53.
    Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office, Edinburgh: Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial. Lancet 2:171–175, 1987Google Scholar
  54. 54.
    Fisher B, Redmond C, Brown A, Fisher ER, Wolmark N, Bowman D, Plotkin D, Wolter J, Bornstein R, Legault-Poisson S, Saffer EA, and other NSABP investigators: Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol 4:459–471, 1986Google Scholar
  55. 55.
    Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet, in pressGoogle Scholar
  56. 56.
    Allred DC, Clark GM, Tandon AK, Molina R, Tormey DC, Osborne CK, Gilchrist KW, Mansour EG, Abeloff M, Eudey L, McGuire WL: HER-2/neu in node-negative breast cancer: Prognostic significance of overexpression influenced by presence of in-situ carcinoma. J Clin Oncol 10:599–605, 1992Google Scholar
  57. 57.
    Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, Henderson IC: c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330:1260–1266, 1994Google Scholar
  58. 58.
    Seidman AD, Baselga J, Yao T-J, Gilewski T, Rosen PP: HER-2/neu overexpression and clinical taxane sensitivity: A multivariate analysis in patients with metastatic breast cancer (Abstract 80). Proc Am Soc Clin Oncol 15:104, 1996Google Scholar
  59. 59.
    Lippman ME, Allegra JC, Thompson EB, Simon R, Barlock A, Green L, Huff KK, Do HM, Aitken SC, Warren R: The relation between estrogen receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer. N Engl J Med 298:1223–1228, 1978Google Scholar
  60. 60.
    Kiang DT, Frenning DH, Goldman AI, Ascensao VF, Kennedy BJ: Estrogen receptors and responses to chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med 299:1330–1334, 1978Google Scholar
  61. 61.
    Clarke CL, Balleine RL, Auchus RJ, Fuqua SAW: Estrogen and progesterone receptor variants in human breast cancer. Current Opin Endocrinol Diabetes 2:398–403, 1995Google Scholar
  62. 62.
    Fuqua SAW: Estrogen and progesterone receptors and breast cancer. In: Harris JR, Lippman ME, Morrow M, Hellman S (eds) Diseases of the Breast. Lippincott-Raven Publishers, Philadelphia PA, 1996, pp 261–271Google Scholar
  63. 63.
    Lehrer SP, Schmutzler RK, Rabin JM, Schachter BS: An estrogen receptor genetic polymorphism and a history of spontaneous abortion: correlation in women with estrogen receptor positive breast cancer but not in women with estrogen receptor negative breast cancer or in women without cancer. Breast Cancer Res Treat 26:175–180, 1993Google Scholar
  64. 64.
    Karnick PS, Kulkarni S, Liu XP, Budd GT, Bukowski RM: Estrogen receptor mutations in tamoxifen-resistant breast cancer. Cancer Res 54:349–353, 1994Google Scholar
  65. 65.
    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 cancer. Cancer Res 52:483–486, 1992Google Scholar
  66. 66.
    Zhang Q, Borg A, Fuqua SAW: An exon 5 deletion variant of the estrogen receptor frequently co-expressed with wild-type estrogen receptor in human breast cancer. Cancer Res 53:5882–5884, 1993Google Scholar
  67. 67.
    Fuqua SAW, Wiltschke C, Castles C, Wolf D, Allred DC: A role for estrogen receptor variants in endocrine resistance. Endocrine-Related Cancer 2:19–25, 1995Google Scholar
  68. 68.
    Wiltschke C, Lemieux P, Wolf DM, Castles CG, Zhang QX, O'Connell P, Allred DC, Fuqua SAW: Isolation of a super-active estrogen receptor variant from premalignant breast lesions (Abstract). Breast Cancer Res Treat 37(Suppl):40, 1996Google Scholar
  69. 69.
    Horwitz KB, McGuire WL, Pearson OH, Segaloff A: Predicting response to endocrine therapy in human breast cancer: A hypothesis. Science 189:726–727, 1975Google Scholar
  70. 70.
    Gross GE, Clark GM, Chamness GC, McGuire WL: Multiple progesterone receptor assays in human breast cancer. Cancer Res 44:836–840, 1984Google Scholar
  71. 71.
    Ravdin PM, Green S, Melink-Dorr T, McGuire WL, Fabian C, Pugh RP, Carter RD, Rivkin SE, Borst JR, Belt RJ, Metch B, Osborne CK: 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 10:1284–1291, 1992Google Scholar
  72. 72.
    Gronemeyer H: Transcription activation by estrogen and progesterone receptors. Ann Rev Genet 25:89–123, 1991Google Scholar
  73. 73.
    Wen DX, Xu YF, Mais DE, Goldman ME, McDonnell DP: The A and B forms of human progesterone receptor operate through distinct signaling pathways within target cells. Mol Cell Biol 14:8356–8364, 1994Google Scholar
  74. 74.
    Tung L, Mohamed MK, Hoeffler JP, Takimoto GS, Horwitz KB: Antagonist-occupied human progester-one B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A receptors. Mol Endocrinol 7:1256–1265, 1993Google Scholar
  75. 75.
    McDonnell DP, Goldman ME: RU486 exerts antiestrogenic activities through a novel progesterone receptor A-form mediated mechanism. J Biol Chem 269:11945–11949, 1994Google Scholar
  76. 76.
    Chalbos D, Galtier F: Differential effect of forms A and B of human progesterone receptor on estradiol-dependent transcription. J Biol Chem 269:23007–23012, 1994Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • C. Kent Osborne
    • 1
  1. 1.Department of Medicine, Division of Medical OncologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA

Personalised recommendations