Skip to main content
SpringerLink
Log in

Molecular action of the estrogen receptor and hormone dependency in breast cancer

  • Review Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

The measurement of estrogen receptor (ER) α in breast cancer tissues is important to discriminate between the hormone dependent and independent tumors. Recently, a second ER, referred to as ERβ, has been identified. The DNA binding domain of ERβ is 96% conserved compared with ERα, and the ligand binding domain shows 53% conserved residues, suggesting that both receptors can bind estrogen responsive elements on target genes, and that they may also bind similar ligand. While both receptors bind to 17β-estradiol with equal affinity, other compounds bind with varying affinities to the two receptors. Since the function of ERβ in breast cancer progression is not well understood, further characterization of the function of ERβ and its isoforms in breast cancer is warranted. Various kinds of cofactors, such as steroid receptor coactivator-1 (SRC-1), transcription intermediary factor 2 (TIF2), and amplified in breast cancer 1 (AIB1), have also been reported. These coactivators interact with nuclear receptors in a ligand-dependent manner and enhance transcriptional activation by the receptor via histone acetylation/methylation and recruitment of additional coactivator, such as CREB binding protein (CBP)/p300.

Thus, action of estrogen is not as simple as thought previously, and is likely influenced by ERβ, its variants and interaction with cofactors. Improved understanding of the ER mechanism may follow from the discovery of these proteins, although their precise roles remain to be determined.

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

Abbreviations

ER:

Estrogen receptor

PgR:

Progesterone receptor

AF-1/-2:

Activation function-1/-2 domain

LBD:

Ligand binding domain

ERE:

Estrogen responsive element

TBP:

TATA binding protein

HAT:

Histone acetyltransferase

DRIP:

Vitamin D receptor interacting proteins

CBP:

CREB binding protein

SRC:

Steroid receptor coactivator

TIF2:

Transcription intermediary factor 2

GRIP 1:

GR-interacting protein 1

ACTR:

hRARβ-stimulatory protein

P/CIP:

CBP-interacting protein

RAC3:

RAR-interacting protein

AIB1:

Amplified in breast cancer

SMRT:

Silencing mediator for retinoid and thyroid-hormone receptors

NcoR:

Nuclear receptor corepressor

HDAC:

Histone deacethylase

SERM:

Selective estrogen receptor modulator

References

  1. Nomura Y, Kobayashi S, Takatani O, Sugano H, Matsumoto K, McGuire WL: Estrogen receptor and endocrine responsiveness in Japanese versus American breast cancer patients.Cancer Res 37: 106–110, 1977.

    PubMed  CAS  Google Scholar 

  2. Bezwoda W, Esser J, Dansey R, Kessel I, Lange M: The value of estrogen and progesterone receptor determinations in advanced breast cancer. Estrogen receptor level but not progesterone receptor level correlates with response to tamoxifen.Cancer 68: 867–872, 1991.

    Article  PubMed  CAS  Google Scholar 

  3. Evans R: The steroid and thyroid hormone receptor superfamily.Science 240: 889–895, 1988.

    Article  PubMed  CAS  Google Scholar 

  4. Green S, Walter P, Greene G, Krust A, Goffin C, Jensen E, Scrace G, Waterfield M, Chambon P: Cloning of the human oestrogen receptor cDNA.J Steroid Biochem 24: 77–83, 1986.

    Article  PubMed  CAS  Google Scholar 

  5. Kato S: Estrogen receptor-mediated cross-talk with growth factor signaling pathways.Breast Cancer 8: 3–9, 2001.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. Tremblay G, Tremblay A, Copeland N, Gilbert DJ, Jenkins NA, Labrie F, Giguere V: Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor β.Mol Endocrinol 11: 353–365, 1997.

    Article  PubMed  CAS  Google Scholar 

  8. Mosselman S, Polman J, Dijkema R: ER-beta: Identification and characterization of a novel human estrogen receptor.FEBS Lett 392: 49–53, 1996.

    Article  PubMed  CAS  Google Scholar 

  9. Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjold M, Gustafsson JA: Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern.J Clim Endocrinol Metab 82: 4258–4265, 1997.

    Article  CAS  Google Scholar 

  10. Menasce L, White G, Harrison C, Boyle, JM: Localization of the estrogen receptor locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH banding technique.Genomics 17: 263–265, 1993.

    Article  PubMed  CAS  Google Scholar 

  11. Ponglikitmongkol M, Green S, Chambon P: Genomic organization of the human oestrogen receptor gene.EMBOJ 7: 3385–3388, 1988.

    CAS  Google Scholar 

  12. Iwase H, Kobayashi S: Alterations and Polymorphisms of the Estrogen Receptor Gene in Breast Cancer.Breast Cancer 4: 57–66, 1997.

    Article  PubMed  Google Scholar 

  13. Chu S, Fuller P: Identification of a splice variant of the rat estrogen receptor beta gene.Mol Cell Endocrinol 132: 195–199, 1997.

    Article  PubMed  CAS  Google Scholar 

  14. Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M: Protein 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 

  15. Leygue E, Dotzlaw H, Watson PH, Murphy LC: Altered estrogen receptor alpha and beta messenger RNA expression during human breast tumorigenesis.Cancer Res 58: 3197–3201, 1998.

    PubMed  CAS  Google Scholar 

  16. Petersen D, Tkalcevic G, Koza-Taylor P, Turi TG, Brown TA: Identification of estrogen receptor beta2, a functional variant of estrogen receptor beta expressed in normal rat tissues.Endocrinology 139: 1082–1092, 1998.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang Q, Hilsenbeck S, Fuqua S, Borg A: Multiple splicing variants of the estrogen receptor are present in individual human breast tumors.J Steroid Biochem Mol Biol 59: 251–260, 1996.

    Article  PubMed  CAS  Google Scholar 

  18. Murphy L, Dotzlaw H, Leygue E, Douglas D, Coutts A, Watson PH: Estrogen receptor variants and mutations.J Steroid Biochem Mol Biol 62: 363–372, 1997.

    Article  PubMed  CAS  Google Scholar 

  19. Omoto Y, Iwase H, Iwata H, Hara Y, Toyama T, Ando Y, Kobayashi S: Expression of estrogen receptor alpha exon 5 and 7 deletion variant in human breast cancers.Breast Cancer 7: 27–31, 2000.

    Article  PubMed  CAS  Google Scholar 

  20. Leclercq G: Molecular forms of the estrogen receptor in breast cancer.J Steroid Biochem Mol Biol 80: 259–272, 2002.

    Article  PubMed  CAS  Google Scholar 

  21. Lonard D, Nawaz Z, Smith C, O’Malley BW: The 26S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation.Mol Cell Biol 5: 939–948, 2000.

    CAS  Google Scholar 

  22. McKenna N, Xu J, Nawaz Z, Tsai SY, Tsai MJ, O’Malley BW: Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions.J Steroid Biochem Mol Biol 69: 3–12, 1999.

    Article  PubMed  CAS  Google Scholar 

  23. Klinge CM: Estrogen receptor interaction with estrogen response elements.Nucleic Acids Res 29: 2905–2919, 2001.

    Article  PubMed  CAS  Google Scholar 

  24. Kushner P, Agard D, Greene G, Scanlan, TS, Shiau, AK, Uht RM, Webb P: Estrogen receptor pathways to AP-l.J Steroid Biochem Mol Biol 74: 311–317, 2000.

    Article  PubMed  CAS  Google Scholar 

  25. Ogawa S, Inoue S, Watanabe T, Hiroi, H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M: The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro.Biochem Biophys Res Commun 243: 122–126, 1998.

    Article  PubMed  CAS  Google Scholar 

  26. Cowley S, Hoare S, Mosselman S, Parker MG: Estrogen receptors alpha and beta form heterodimers on DNA.J Biol Chem 272: 19858–19862, 1997.

    Article  PubMed  CAS  Google Scholar 

  27. Pettersson K, Grandien K, Kuiper G, Gustafsson JA: Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha.Mol Endocrinol 11: 1486–1496, 1997.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. Dotzlaw H, Leygue E, Watson PH, Murphy LC: Expression of estrogen receptor-beta in human breast tumors.J Clin Endocrinol Metab 82: 2371–2374, 1997.

    Article  PubMed  CAS  Google Scholar 

  30. 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 

  31. 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 

  32. Iwao K, Miyoshi Y, Egawa C, Ikeda N, Noguchi S: Quantitative analysis of estrogen receptor-beta mRNA and its variants in human breast cancers.Int J Cancer 88: 733–736, 2000.

    Article  PubMed  CAS  Google Scholar 

  33. 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 

  34. Pavao M, Traish AM: Estrogen receptor antibodies: specificity and utility in detection, localization and analyses of estrogen receptor alpha and beta.Steroids 66: 1–16, 2001.

    Article  PubMed  CAS  Google Scholar 

  35. Roger P, Sahla ME, Makela S, Gustafsson JA, Baldet P, Rochefort H: Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors.Cancer Res 61: 2537–2541, 2001.

    PubMed  CAS  Google Scholar 

  36. Skliris GP, Carder PJ, Lansdown MR, Speirs V: Immunohistochemical detection of ERbeta in breast cancer: towards more detailed receptor profiling?Br J Cancer 84: 1095–1098, 2001.

    Article  PubMed  CAS  Google Scholar 

  37. Saunders PT, Millar MR, Williams K, Macpherson S, Bayne C, O’Sullivan C, Anderson TJ, Groome NP, Miller WR: Expression of oestrogen receptor beta (ERbetal) protein in human breast cancer biopsies.Br J Cancer 86: 250–256, 2002.

    Article  PubMed  CAS  Google Scholar 

  38. Gustafsson JA, Warner M: Estrogen receptor beta in the breast: role in estrogen responsiveness and development of breast cancer.J Steroid Biochem Mol Biol 74: 245–248, 2000.

    Article  PubMed  CAS  Google Scholar 

  39. Knowlden J, Gee J, Robertson J, Ellis IO, Nicholson RI: A possible divergent role for the oestrogen receptor alpha and beta subtypes in clinical breast cancer.Int J Cancer 89: 209–212, 2000.

    Article  PubMed  CAS  Google Scholar 

  40. Speirs V, Kerin M: Prognostic significance of oestrogen receptor beta in breast cancer.Br J Surg 87: 405–409, 2000.

    Article  PubMed  CAS  Google Scholar 

  41. Hu YF, Lau KM, Ho SM, Russo J: Increased expression of estrogen receptor beta in chemically transformed human breast epithelial cells.Int J Oncol 12: 1225–1228, 1998.

    PubMed  CAS  Google Scholar 

  42. Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lakins J, Lupu R: Expression and regulation of estrogen receptor beta in human breast tumors and cell lines.Oncol Rep 7: 157–167, 2000.

    PubMed  CAS  Google Scholar 

  43. 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 

  44. 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 

  45. 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 clinicopathological factors in breast cancers.Eur J Cancer 38: 380–386, 2002.

    Article  PubMed  CAS  Google Scholar 

  46. Fuqua SA, Schiff R, Parra I, Friedrichs WE, Su JL, McKee DD, Slentz-Kesler K, Moore LB, Willson TM, Moore JT: Expression of wild-type estrogen receptor beta and variant isoforms in human breast cancer.Cancer Res 59: 5425–5428, 1999.

    PubMed  CAS  Google Scholar 

  47. Iwase H, Omoto Y, Toyama T, Hara Y, Iwata H, Kobayashi S: Clinical Significance of Estrogen Receptor beta in Breast Cancer.Breast Cancer 6: 325–330, 1999.

    Article  PubMed  Google Scholar 

  48. Palmieri C, Cheng GJ, Saji S, Zelada-Hedman M, Warri A, Weihua Z, Van Noorden S, Wahlstrom T, Coombes RC, Warner M, Gustafsson JA: Estrogen receptor beta in breast cancer.Endocr Relat Cancer 9: 1–13, 2002.

    Article  PubMed  CAS  Google Scholar 

  49. Horwitz K, Jackson T, Bain D, Richer JK, Takimoto GS, Tung L: Nuclear receptor coactivators and corepressors.Mol Endocrinol 10: 1167–1177, 1996.

    Article  PubMed  CAS  Google Scholar 

  50. Greenblatt J: Roles of TFIID in transcriptional initiation by RNA polymerase II.Cell 66: 1067–1070, 1991.

    Article  PubMed  CAS  Google Scholar 

  51. Buratowski S: The basics of basal transcription by RNA polymerase II.Cell 77: 1–3, 1994.

    Article  PubMed  CAS  Google Scholar 

  52. Lee S, Hahn S: Model for binding of transcription factor TFIIB to the TBP-DNA complex.Nature 376: 609–612, 1995.

    Article  PubMed  CAS  Google Scholar 

  53. Guan X, Xu J, Anzick S, Zhang H, Trent JM, Meltzer PS: Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer.Cancer Res 56: 3446–3450, 1996.

    PubMed  CAS  Google Scholar 

  54. Loe C, Chen J: The SRC family of nuclear receptor coactivators.Gene 245: 1–11, 2002.

    Google Scholar 

  55. Smith C, Onate SA, Tsai MJ, O’Malley BW: CREB binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptor-dependent transcription.Proc Natl Acad Sci USA 93: 8884–8888, 1996.

    Article  PubMed  CAS  Google Scholar 

  56. Onate S, Tsai S, Tsai M, O’Malley BW: Sequence and characterization of a coactivator for the steroid hormone receptor superfamily.Science 270: 1354–1357, 1995.

    Article  PubMed  CAS  Google Scholar 

  57. Voegel J, Heine M, Zechel C, Chambon P, Gronemeyer H: TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors.EMBO J 15: 3667–3675, 1996.

    PubMed  CAS  Google Scholar 

  58. Takeshita A, Yen P, Misiti S, Cardona GR, Liu Y, Chin WW: Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivator.Endocrinology 137: 3594–3597, 1996.

    Article  PubMed  CAS  Google Scholar 

  59. Anzick S, Kononen J, Walker R, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS: AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer.Science 277: 965–968, 1997.

    Article  PubMed  CAS  Google Scholar 

  60. Bouras T, Southey M, Venter D: Overexpression of the steroid receptor coactivator AIB1 in breast cancer correlates with the absence of estrogen and progesterone receptors and positivity for p53 and HER2/ neu.Cancer Res 61: 903–907, 2001.

    PubMed  CAS  Google Scholar 

  61. Hara Y, Yamashita H, Toyama T, Sugiura H, Kobayashi S, Iwase H: Clinical significance of AIB1 expression in human breast cancers.Proceeding, The 10th Anual meeting of the Japanese Breast Cancer Scociety 10: 155, 2002.

    Google Scholar 

  62. Jackson T, Richer J, Bain D, Takimoto GS, Tung L, Horwitz K: 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, 1997.

    Article  PubMed  CAS  Google Scholar 

  63. Graham J, Bain D, Richer J, Jackson TA, Tung L, Horwitz KB: Nuclear receptor conformation, coregulators, and tamoxifen-resistant breast cancer.Steroids 65: 579–584, 2000.

    Article  PubMed  CAS  Google Scholar 

  64. Burger H: Selective oestrogen receptor modulators.Horm Res 53: 25–29, 2000.

    Article  PubMed  CAS  Google Scholar 

  65. Smith C, Nawaz Z, BW OM: Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen.Mol Endocrinol 11: 657–666, 1997.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology and Endocrinology, Nagoya City University Graduate School of Medical Sciences, Japan

    Hirotaka Iwase

Authors
  1. Hirotaka Iwase
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hirotaka Iwase.

Additional information

Reprint requests to Hirotaka Iwase, Department of Oncology and Endocrinology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-ku, Nagoya 467-8601, Japan.

About this article

Cite this article

Iwase, H. Molecular action of the estrogen receptor and hormone dependency in breast cancer. Breast Cancer 10, 89–96 (2003). https://doi.org/10.1007/BF02967632

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02967632

Key words

Search

Navigation