Skip to main content
SpringerLink
Log in

The Normal and Malignant Mammary Gland: A Fresh Look with ERβ Onboard

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Estrogens are important for the development and function of the normal mammary gland as well as for development of mammary cancer. The frontline therapy for treatment of estrogen receptor (ERα)4 positive breast cancer is antiestrogens. A second estrogen receptor (ERβ) is also expressed in the breast but it has not been measured because it is not detected by the immunoassays used to detect ERα. In many cell systems ERβ has actions which are opposite to those of ERα and this finding has raised questions about the role of ERβ in the development and treatment of breast cancer.

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. G. G. Kuiper, E. Enmark, M. Pelto-Huikko, S. Nilsson, and J-Å. Gustafsson (1996). Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. U.S.A. 93:5925–5930.

    Google Scholar 

  2. P. Webb, G. N. Lopez, R. M. Uht, and P. J. Kushner (1995). Tamoxifen activation of the estrogen receptor/AP1 pathway: Potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol. Endocrinol. 9:443–456.

    Google Scholar 

  3. K. Paech, P. Webb, G. G. Kuiper, S. Nilsson, J-Å. Gustafsson, P. J. Kushner, and T. S. Scalan (1997). Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277:1508–1510.

    Google Scholar 

  4. G. G. Kuiper and J-Å. Gustafsson (1997). The novel estrogen receptorβ subtype: Potential role in the cell-and promoterspecific actions of estrogens and anti-estrogens. FEBS Lett. 410:87–90.

    Google Scholar 

  5. C. Y. Chang, J. D. Norris, H. Gron, L. A. Paige, P. T. Hamilton, D. J. Kenan, D. Fowlkes, and D. P. McDonnell (1999). Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: Discovery of peptide antagonists of estrogen receptors α and β. Mol. Cell. Biol. 19:8226–8239.

    Google Scholar 

  6. M. J. Meyers, J. Sun, K. E. Carlson, B. S. Katzenellenbogen, and J. A. Katzenellenbogen (1999). Estrogen receptor subtype-selective ligands: Asymmetric synthesis and biological evaluation of cis-and trans-5,11-dialkyl-5,6,11, 12-tetrahydrochrysenes. J. Med. Chem. 42:2456–2468.

    Google Scholar 

  7. J. Sun, M. J. Meyers, B. E. Fink, R. Rajendran, J. A. Katzenellenbogen, and B. S. Katzenellenbogen (1999). Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor-alpha or estrogen receptor-beta. Endocrinology 140:800–804.

    Google Scholar 

  8. E. Enmark, M. Pelto-Huikko, K. Grandien, G. Fried, S. Langerkrantz, J. Langerkrantz, M. Nordenskjold and J-Å. Gustafsson (1997). Human estrogen receptor β-gene structure, chromosomal localization and expression pattern. J. Clin. Endocrinol. Metab. 82:4258–4265.

    Google Scholar 

  9. G. B. Tremblay, A. Tremblay, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, F. Labrie, and V. Gigurere (1997). Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor β. Mol. Endocrinol. 11:352–365.

    Google Scholar 

  10. T. Todo, S. Adachi, and K. Yamauchi (1996). Molecular cloning and characterization of Japanese eel estrogen receptor cDNA. Mol. Cell Endocrinol. 119:37–45.

    Google Scholar 

  11. M. Tsai and B. W. O'Malley (1994). Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Ann. Rev. Biochem. 63:451–486.

    Google Scholar 

  12. G. G. Kuiper, J. G. Lemmen, B. Carlsson, J. C. Corton, S. H. Safe, P. T. van der Saag, and J-Å. Gustafsson (1998). Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 139: 4252–4263.

    Google Scholar 

  13. A. Tremblay, G. B. Tremblay, F. Labrie, and V. Giguere (1999). Ligand-independent recruitment of SRC-1 to estrogen receptor β through phosphorylation of activation function AF-1. Mol. Cell 3:513–519.

    Google Scholar 

  14. B. MacMahon, P. Cole, and J. Brown (1973). Etiology of human breast cancer: A review. J. Natl. Cancer Inst. 50:21.

    Google Scholar 

  15. M. J. Messina (1999). Legumes and soybeans: Overview of their nutritional profiles and health effects. Amer. J. Clin. Nutrit. 70:439S–450S.

    Google Scholar 

  16. A. M. Brzozowski, A. C. W. Pike. Z. Dauter R. E. Hubbard, T. Bonn, O Engstrom, L. Ohman, G. Greene, J-Å.Gustafsson, and M. Carlquist (1997). Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758.

    Google Scholar 

  17. A. C. W., Pike, A. M. Brzozowski, R. E. Hubbard, T. Bonn, A. G. Thorsell, O. Engstrom, J. Ljunggren, J-Å. Gustafsson, and M. Carlquist (1999). Structure of the ligand-binding domain of oestrogen receptor β in the presence of a partial agonist and a full antagonist. EMBO J. 18:4608–4618.

    Google Scholar 

  18. R. B. Clarke, A. Howell, C. S. Potten, and E. Anderson (1997). Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res. 57, 4987–4991.

    Google Scholar 

  19. R. B. Clark, A. Howell, and E. Anderson (1997). Estrogen sensitivity of normal human breast tissue in vivo and implanted into athymic nude mice: Analysis of the relationship between estrogen-induced proliferation and progesterone receptor expression. Breast Cancer Res. Treat. 45: 121–133.

    Google Scholar 

  20. S. Saji, E. V. Jensen, S. Nilsson, T. Rylander, M. Warner, and J-Å. Gustafsson (2000). Estrogen receptors α and β in the rodent mammary gland. Proc. Natl. Acad. Sci. U.S.A. 97:337–342.

    Google Scholar 

  21. R. B. Dickson and M. E. Lipman (1995). Growth factors in breast cancer. Endocrine Rev. 16: 559–598.

    Google Scholar 

  22. S. Chu, and P. J. Fuller (1997). Identification of a splice variant of the rat estrogen receptor β gene. Mol. Cell. Endocrinol. 132:195–199.

    Google Scholar 

  23. B. Hanstein, H. Liu, M. Yancisin, and M. Brown (1999). Functional analysis of a novel estrogen receptor-β-isoform. Mol. Endocrinol. 13:129–137.

    Google Scholar 

  24. K. Maruyama, H. Endoh, H. Sasaki-Iwaoka, H. Kanou, E. Shimaya, S. Hashimoto, S. Kato, and H. Kawashima (1998). A novel isoform of rat estrogen receptor _ with 18 amino acid insertion in the ligand binding domain is a putative dominant negative regular of estrogen action. Biochem. Biophys. Res. Comm. 246:142–147.

    Google Scholar 

  25. C. A. Lange, J. K. Richer, and K. B. Horwitz (1999). Hypothesis: Progesterone primes breast cancer cells for cross-talk with proliferative or antiproliferative signals. Mol. Endocrinol. 13:829–836.

    Google Scholar 

  26. K. Pettersson, K. Grandien, G. G. Kuiper, and J-Å. Gustafsson (1997). Mouse estrogen receptor β forms estrogen response element-binding heterodimers with estrogen receptor α. Mol. Endocrinol. 11:1486–1496.

    Google Scholar 

  27. S. Ali and R. C. Coombes (2000). Estrogen reoeptor α in human breast cancer: Occurrence and significance. J. Mam. Gland Biol. Neoplasia 5(3) (in press).

  28. J-Å. Gustafsson (1998). Therapeutic potential of selective estrogen receptor modulators. Curr. Opin. Chem. Biol. 2:508–511.

    Google Scholar 

  29. S. Ogawa, S. Inoue, T. Watanabe, H. Hiroi, A. Orimo, T. Hosoi, Y. Ouchi, and M. Muramatsu (1998). The complete primary structure of human estrogen receptorβ (hEβ) and its heterodimerization with ERα in vivo and in vitro. Biochem. Biophys. Res. Comm. 243: 122–126.

    Google Scholar 

  30. S. Ogawa, S. Inoue, T. Watanabe, A. Orimo, T. Hosoi, Y. Ouchi, and M. Muramatsu (1998). Molecular cloning and characterization of human estrogen receptor flcx:Apotential inhibitor of estrogen action in human. Nucleic Acids Res. 26:3505–3512.

    Google Scholar 

  31. T. A. Jarvinen, M. Pelto-Huikko, K. Holli, and J. Isola (2000). Estrogen receptor β is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Amer. J. Pathol. 156:29–35.

    Google Scholar 

  32. L. C. Murphy, H. Dotzlaw, E. Leygue, A. Coutts, and P. Watson (1998). The pathophysiological role of estrogen receptor variants in human breast cancer. J. Steroid Biochem. Mol. Biol. 65: 175–180.

    Google Scholar 

  33. V. Speirs, C. Malone, D. S. Walton, M. J. Kerin, and S. L. Atkin (1999). Increased expression of estrogen receptor _ mRNA in tamoxifen-resistant breast cancer patients Cancer Res. 59:5421–5424.

    Google Scholar 

  34. H. Dotzlaw, E. Leygue, P. H. Watson, and L. C. Murphy (1999). Estrogen receptorβ messenger RNA expression in human breast tumor biopsies: Relationship to steroid receptor status and regulation by progestins. Cancer Res. 59:529–532.

    Google Scholar 

  35. L. Klein-Hitpass, M. Schorrp, U. Wagner, and G. U. Ryffel (1986). An estrogen-responsive element derived from the 5_ flanking region of the xenopus vitellogenin A2 gene functions in transfected human cells. Cell 46:1053–1061.

    Google Scholar 

  36. M. Beato (1989). Gene regulation by steroid hormones. Cell 56:335–344.

    Google Scholar 

  37. A. Ray, K. E. Prefontaine, and P. Ray (1994). Down-modulation of interleukin-6 gene expression by estradiol 17β in the absence of high affinityDNAbinding by the estrogen receptor. J. Biol. Chem. 269: 12940–12946.

    Google Scholar 

  38. R. Galienand and T. Garcia (1997). Estrogen receptor impairs interleukin-6 expression by preventing protein binding on the NF-κB site. Nucleic Acids Res. 25:2424–2429.

    Google Scholar 

  39. S. R. Batistuzzo de Medeiros, G. Krey, A. K. Hihi, and W. Wahli (1997). Functional interaction between the estrogen receptor and the transcription activator Sp1 regulate the estrogen-dependent transcriptional activity of the vitellogenin A1 promoter. J. Biol. Chem. 272:18250–18260.

    Google Scholar 

  40. W. Porter, B. Saville, D. Hoivik, and S. Safe (1999). Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol. Endocrinol. 11:1569–1580.

    Google Scholar 

  41. C. Qin, P. Singh, and S. Safe (1999). Transcriptional activation of insulin-like growth factor-binding protein-4 by 17β-estradiol in MCF-7 cells: Role of estrogen receptor-SP1 complexes. Endocrinology 140:2501–2508.

    Google Scholar 

  42. G. Sun, W. Porter, and S. Safe (1998). Estrogen-induced retinoic acid receptor α1 gene expression: Role of estrogen receptor-Sp1 complex. Mol. Endocrinol. 12:882–890.

    Google Scholar 

  43. A. Zou, K. B. Marschke, K. E. Arnold, E. M. Berger. P. Fitzgerald, D. E. Mais, and E. A. Allegretto (1999). Estrogen receptor activates the human retinoic acid receptor-1 promoter in response to tamoxifen and other estrogen receptor antagonists, but not in response to estrogen. Mol. Endocrinol. 13: 418–430.

    Google Scholar 

  44. W. Y. Zhu, C. S. Jones, S. Amin, K. Matsukuma, M. Haque, V. Vuligonda, R. A. Chandraratna, and L. M. De Luca (1999). Retinoic acid increases tyrosine phosphorylation of focal adhesion kinase and paxillin in MCF-7 human breast cancer cells. Cancer Res. 59:85–90.

    Google Scholar 

  45. P. J. Daschner, H. P. Ciolino, C. A. Plouzek, and G. C. Yeh (1999). Increased AP-1 activity in drug resistant human breast cancer MCF-7 cells. Breast Cancer Res. Treat. 53:229–240.

    Google Scholar 

  46. B. Rockhill, C. R. Weinberg, and B. Newman (1998). Population attributable fraction estimation for established breast cancer risk factors: Considering the issues of high prevalence and unmodifiability Am. J. Epidemiol. 147:826–833.

    Google Scholar 

  47. P. Montero, C. Bernis, M. Loukid, K. Hilali, and A. Baali Characteristics of menstrual cycles in Moroccan girls: Prevalence of dysfunctions and associated behaviors. Ann. Human Biol. 26:243–249.

  48. B. A. Stoll (1998). Western diet, early puberty, and breast cancer risk. Breast Cancer Res. Treat. 49:187–193.

    Google Scholar 

  49. P. L. Horn-Ross, M. Morrow, and B. M. Ljung (1999). Menstrual and reproductive factors for salivary gland cancer risk in women. Epidemiology 10:528–530.

    Google Scholar 

  50. M. H. Moen and B. Schei (1997). Epidemiology of endometriosis in a Norwegian county. Acta Obstet. Gynecol. Scand. 76:559–562.

    Google Scholar 

  51. S. D. Thompson (1998). Ovarian cancer screening: A primary care guide. Lippincott's Primary Care Practice 2:244–250.

    Google Scholar 

  52. Z. Weihua, S. Saji, S Mekinen, G. Cheng, E. V. Jensen, M. Warner, and J-Å. Gustafsson (2000). ERβ, a modulator of ERα in the uterus. Proc. Natl. Acad. Sci. U.S.A. 97:5936–5941.

    Google Scholar 

  53. Z. Weihua, S. Makela, L. C. Andersson, S. Salmi, S. Saji, S. Nilsson, M. Warner, and J-Z. Gustafsson (undated). Estrogen receptor _ knock out leads to prostate hyperplasia and dysplasia PIN lesions. Submitted to Nature Med..

  54. G. Cheng, S. Mekinen, Z. Weihua, S. Mekela, S. Saji, O. Hovatta, M. Warner, and J-Z. Gustafsson. (undated). Loss of down regulation of androgen receptor: The cause of ovarian dysfunction in estrogen receptor β knock out mice. Submitted to Mol. Endocrinol.

Download references

Author information

Authors and Affiliations

  1. Department of Bioscience, Karolinska Institute, NOVUM, Huddinge, S-141 86, Sweden

    Margaret Warner

  2. Department of Medical Nutrition, Karolinska Institute, NOVUM, Huddinge, S-141 86, Sweden

    Shigehira Saji

  3. Department of Bioscience, Karolinska Institute, NOVUM, Huddinge, S-141 86, Sweden

    Jan-Åke Gustafsson

Authors
  1. Margaret Warner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shigehira Saji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan-Åke Gustafsson
    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

Warner, M., Saji, S. & Gustafsson, JÅ. The Normal and Malignant Mammary Gland: A Fresh Look with ERβ Onboard. J Mammary Gland Biol Neoplasia 5, 289–294 (2000). https://doi.org/10.1023/A:1009598828267

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009598828267

Search

Navigation