Skip to main content

Advertisement

SpringerLink
Log in

Estrogen and progesterone receptor isoforms: clinical significance in breast cancer

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The identification and exploitation of biomarkers that may predict response to anti-cancer treatments has the capacity to revolutionize the way that patients with cancer are treated. In breast cancer, the estrogen receptor (ER) and the progesterone receptor (PgR) are known to have a significant predictive value in determining sensitivity to endocrine therapies. Tumor expression of ER or PgR is known to affect clinical outcome and this information is often used to determine a patient's optimal treatment regimen. However, the measurement of ER and PgR alone is more complex than originally thought and the impact of the recently identified isoforms of ER (ERα and ERβ) and PgR (PgRA and PgRB), as well as several variant and mutant forms, upon the choice of treatment remains unclear. Therefore, ER and PgR expression alone are unlikely to determine a patient's optimal treatment regimen, particularly when the amount of ‘cross-talk’ between different pathways, such as the epidermal growth factor receptor pathway, is considered. In order to account for the complex cell-signaling environment that occurs in breast cancer, multifactorial techniques are needed to analyze tumor biomarker expression. The recent advances in genomic- or proteomic-based approaches has enabled molecular portraits of breast cancers to be painted, allowing biomarkers of response and prognosis to be identified and characterized more accurately than before. In the future, patients could be treated according to the molecular portrait of their tumor biomarker expression, maximizing the therapeutic benefit that each patient receives.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Breast Cancer Version 1.2003.Clinical Practice Guidelines in Oncology v.1.2003.National Comprehensive Cancer Network,2003

  2. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA:Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930,1996

    Article  PubMed  CAS  Google Scholar 

  3. Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS:Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 277:1508–1510,1997

    Article  PubMed  CAS  Google Scholar 

  4. Jensen EV, Cheng G, Palmieri C, Saji S, Makela S, Van Noorden S, Wahlstrom T, Warner M, Coombes RC, Gustafsson JA:Estrogen receptors and proliferation mark-ers in primary and recurrent breast cancer. Proc Natl Acad Sci USA 98:15197–15202,2001

    Article  PubMed  CAS  Google Scholar 

  5. Speirs V, Parkes AT, Kerin MJ, Walton DS, Carleton PJ, Fox JN, Atkin SL:Coexpression of estrogen receptor alpha and beta:poor prognostic factors in human breast cancer? Cancer Res 59:525–528,1999

    PubMed  CAS  Google Scholar 

  6. Speirs V, Skliris GP, Burdall SE, Carder PJ:Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. J Clin Pathol 55:371–374,2002

    PubMed  CAS  Google Scholar 

  7. Hayashi SI, Eguchi H, Tanimoto K, Yoshida T, Omoto Y, Inoue A, Yoshida N, Yamaguchi Y:The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application. Endocr Relat Cancer 10:193–202,2003

    Article  PubMed  CAS  Google Scholar 

  8. Allred DC, Mohsin SK:Biological features of human premalignant breast disease.In:Harris JR, Lippman ME, Morrow M, Osborne CK (eds) Diseases of the Breast. 2nd edn.Lippincott-Raven Publishers,1999,pp. 355–366

  9. Fuqua SA, Schiff R, Parra I, Moore JT, Mohsin SK, Osborne CK, Clark GM, Allred DC:Estrogen receptor beta protein in human breast cancer:correlation with clinical tumor parameters. Cancer Res 63:2434–2439, 2003

    PubMed  CAS  Google Scholar 

  10. Shaaban AM, O'Neill PA, Davies MP, Sibson R, West CR, Smith PH, Foster CS:Declining estrogen receptor-beta expression de nes malignant progression of human breast neoplasia. Am J Surg Pathol 27:1502–1512,2003

    Article  Google Scholar 

  11. Jarvinen TA, Pelto-Huikko M, Holli K, Isola J:Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status,grade,and proliferation rate in breast cancer. Am J Pathol 156:29–35,2000

    PubMed  CAS  Google Scholar 

  12. Skliris GP, Carder PJ, Lansdown MR, Speirs V:Immuno-histochemical detection of ERbeta in breast cancer:towards more detailed receptor pro ling?Br J Cancer 84:1095–1098,2001

    Article  PubMed  CAS  Google Scholar 

  13. Skliris GP, Munot K, Bell SM, Carder PJ, Lane S, Horgan K, Lansdown MR, Parkes AT, Hanby AM, Markham AF, Speirs V:Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol 201:213–220,2003

    Article  PubMed  CAS  Google Scholar 

  14. Early Breast Cancer Trialists 'Collaborative Group: Tamoxifen for early breast cancer:an overview of the randomised trials. Lancet 351:1451–1467,1998

    Article  Google Scholar 

  15. Hilsenbeck SG, Ravdin PM, de Moor CA, Chamness GC, Osborne CK, Clark GM:Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat 52:227–237,1998

    Article  PubMed  CAS  Google Scholar 

  16. Omoto Y, Eguchi H, Yamamoto-Yamaguchi Y, Hayashi S: Estrogen receptor (ER)beta1 and ERbetacx/beta2 inhibit ERalpha function differently in breast cancer cell line MCF7. Oncogene 22:5011–5020,2003

    Article  PubMed  CAS  Google Scholar 

  17. Omoto Y, Inoue S, Ogawa S, Toyama T, Yamashita H, Muramatsu M, Kobayashi S, Iwase H:Clinical value of the wild-type estrogen receptor beta expression in breast cancer. Cancer Lett 163:207–212,2001

    Article  PubMed  CAS  Google Scholar 

  18. Foekens JA, Look MP, Bolt-de Vries J, Meijer-van Gelder ME, van Putten WL, Klijn JG:Cathepsin-D in primary breast cancer:prognostic evaluation involving 2810 patients. Br J Cancer 79:300–307,1999

    Article  PubMed  CAS  Google Scholar 

  19. Mann S, Laucirica R, Carlson N, Younes PS, Ali N, Younes A, Li Y, Younes M:Estrogen receptor beta expression in invasive breast cancer. Hum Pathol 32:113–118,2001

    Article  PubMed  CAS  Google Scholar 

  20. Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M:Molecular cloning and characterization of human estrogen receptor betacx:a potential inhibitor of estrogen action in human. Nucleic Acids Res 26:3505–3512,1998

    Article  PubMed  CAS  Google Scholar 

  21. Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lupu R: Expression of estrogen receptor beta messenger RNA variant in breast cancer. Cancer Res 58:210–214,1998

    PubMed  CAS  Google Scholar 

  22. Fuqua SA, Fitzgerald SD, Allred DC, Elledge RM, Nawaz Z, McDonnell DP, O'Malley BW, Greene GL, McGuire WL:Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors. Cancer Res 52: 483–486,1992

    PubMed  CAS  Google Scholar 

  23. Garcia Pedrero JM, Zuazua P, Martinez-Campa C, Lazo PS, Ramos S:The naturally occurring variant of estrogen receptor (ER)ERDeltaE7 suppresses estrogen-dependent transcriptional activation by both wild-type ERalpha and ERbeta. Endocrinology 144:2967–2976,2003

    Article  PubMed  CAS  Google Scholar 

  24. Omoto Y, Kobayashi S, Inoue S, Ogawa S, Toyama T, Yamashita H, Muramatsu M, Gustafsson JA, Iwase H: Evaluation of oestrogen receptor beta wild-type and variant protein expression,and relationship with clinicopathologi-cal factors in breast cancers. Eur J Cancer 38:380–386,2002

    Article  PubMed  CAS  Google Scholar 

  25. Saji S, Omoto Y, Shimizu C, Horiguchi S, Watanabe T, Funata N, Hayash S, Gustafsson JA, Toi M:Clinical impact of assay of estrogen receptor beta cx in breast cancer. Breast Cancer 9:303–307,2002

    Article  PubMed  Google Scholar 

  26. Fuqua SA, Wiltschke C, Zhang QX, Borg A, Castles CG, Friedrichs WE, Hopp T, Hilsenbeck S, Mohsin S, O'Connell P, Allred DC:A hypersensitive estrogen receptor-alpha mutation in premalignant breast lesions. Cancer Res 60: 4026–4029,2000

    PubMed  CAS  Google Scholar 

  27. Zhang Z, Yamashita H, Toyama T, Omoto Y, Sugiura H, Hara Y, Haruki N, Kobayashi S, Iwase H:Estrogen receptor alpha mutation (A-to-G transition at nucleotide 908)is not found in different types of breast lesions from Japanese women. Breast Cancer 10:70–73,2003

    Article  PubMed  Google Scholar 

  28. Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC, Clark GM, Schiff R:Role of the estrogen receptor coactivator AIB1 (SRC-3)and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 95:353–361,2003

    Article  PubMed  CAS  Google Scholar 

  29. Horwitz KB, Alexander PS:In situ photolinked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and trans-location. Endocrinology 113:2195–2201,1983

    Article  PubMed  CAS  Google Scholar 

  30. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P:Two distinct estrogen-regu-lated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 9:1603–1614,1990

    PubMed  CAS  Google Scholar 

  31. Bain DL, Franden MA, McManaman JL, Takimoto GS, Horwitz KB:The N-terminal region of the human progesterone A-receptor.Structural analysis and the influence of the DNAbinding domain. J Biol Chem 275:7313–7320,2000

    Article  PubMed  CAS  Google Scholar 

  32. Ariga N, Suzuki T, Moriya T, Kimura M, Inoue T, Ohuchi N, Sasano H:Progesterone receptor A and B isoforms in the human breast and its disorders. Jpn J Cancer Res 92: 302–308,2001

    PubMed  CAS  Google Scholar 

  33. Mote PA, Leary JA, Avery KA, Sandelin K, Chenevix-Trench G, Kirk JA, Clarke CL:Germ-line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen-responsive proteins and the predominance of progesterone receptor A. Genes Chromo-somes Cancer 39:236–248,2004

    Article  CAS  Google Scholar 

  34. Hopp TA, Weiss HL, Hilsenbeck SG, Allred DC, Horwitz KB, Fuqua SAW:Breast cancer patients with progesterone receptor PR-A-rich tumors have poorer disease-free survi-val rates. Clin Cancer Res 10:2751–2760,2004

    Article  PubMed  CAS  Google Scholar 

  35. Richer JK, Lange CA, Wierman AM, Brooks KM, Tung L, Takimoto GS, Horwitz KB:Progesterone receptor variants found in breast cells repress transcription by wild-type receptors. Breast Cancer Res Treat 48:231–241,1998

    Article  PubMed  CAS  Google Scholar 

  36. Hisatomi H, Kohno N, Wakita K, Nagao K, Hirata H, Hikiji K, Harada S:Novel alternatively spliced variant with a deletion of 52 BP in exon 6 of the progesterone receptor gene is observed frequently in breast cancer tissues. Int J Cancer 105:182–185,2003

    Article  PubMed  CAS  Google Scholar 

  37. Wang-Gohrke S, Chang-Claude J, Becher H, Kieback DG, Runnebaum IB:Progesterone receptor gene polymorphism is associated with decreased risk for breast cancer by age 50. Cancer Res 60:2348–2350,2000

    PubMed  CAS  Google Scholar 

  38. Manolitsas TP, Engleeld P, Eccles DM, Campbell IG:No association of a 306-bp insertion polymorphism in the progesterone receptor gene with ovarian and breast cancer. Br J Cancer 75:1398–1399,1997

    PubMed  CAS  Google Scholar 

  39. Lancaster JM, Berchuck A, Carney ME, Wiseman R, Taylor JA:Progesterone receptor gene polymorphism and risk for breast and ovarian cancer. Br J Cancer 78: 277,1998

    Article  PubMed  CAS  Google Scholar 

  40. Spurdle AB, Hopper JL, Chen X, McCredie MR, Giles GG, Venter DJ, Southey MC, Chenevix-Trench G:The progesterone receptor exon 4 Val660Leu G/T polymor-phism and risk of breast cancer in Australian women. Cancer Epidemiol Biomarkers Prev 11:439–443,2002

    PubMed  CAS  Google Scholar 

  41. Nicholson RI, Gee JMW, Knowlden J, McClelland R, Madden T, Barrow D, Hutcheson I:The biology of antihormone failure in breast cancer. Breast Cancer Res Treat 80(Suppl 1):S29-S34,2003

    Article  PubMed  CAS  Google Scholar 

  42. Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Elledge R, Mohsin S, Osborne CK, Chamness GC, Allred DC, O'Connell P:Gene expression pro ling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 362: 362–369,2003

    Article  PubMed  CAS  Google Scholar 

  43. van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH:Gene expression pro ling predicts clinical outcome of breast cancer. Nature 415:530–536,2002

    Article  Google Scholar 

  44. van de Vijver MJ, He YD, van 't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R:A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347: 1999–2009,2002

    Article  Google Scholar 

  45. Somiari RI, Sullivan A, Russell S, Somiari S, Hu H, Jordan R, George A, Katenhusen R, Buchowiecka A, Arciero C, Brzeski H, Hooke J, Shriver C:High-throughput proteomic analysis of human in ltrating ductal carcinoma of the breast. Proteomics 3:1863–1873,2003

    Article  PubMed  CAS  Google Scholar 

  46. Celis JE, Gromov P, Gromova I, Moreira JM, Cabezon T, Ambartsumian N, Grigorian M, Lukanidin E, Thor Straten P, Guldberg P, Bartkova J, Bartek J, Lukas J, Lukas C, Lykkesfeldt A, Jaattela M, Roepstor P, Bolund L, Orntoft T, Brunner N, Overgaard J, Sandelin K, Blichert-Toft M, Mouridsen H, Rank FE:Integrating proteomic and functional genomic technologies in discovery-driven trans-lational breast cancer research. Mol Cell Proteomics 2:369–377,2003

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Breast Center, Baylor College of Medicine, TX, USA

    Suzanne AW Fuqua & Yukun Cui

Authors
  1. Suzanne AW Fuqua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yukun Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fuqua, S.A., Cui, Y. Estrogen and progesterone receptor isoforms: clinical significance in breast cancer. Breast Cancer Res Treat 87, 3–10 (2004). https://doi.org/10.1007/s10549-004-1577-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-004-1577-4

Search

Navigation