Breast Cancer Research and Treatment

, Volume 109, Issue 2, pp 241–250 | Cite as

Estrogen receptor beta increases the efficacy of antiestrogens by effects on apoptosis and cell cycling in breast cancer cells

  • Leslie Hodges-Gallagher
  • Cathleen D. Valentine
  • Suzy El Bader
  • Peter J. Kushner
Preclinical Study


Clinical evidence indicates that higher levels of estrogen receptor beta (ERβ) predicts improved disease-free and overall survival in patients treated with adjuvant tamoxifen therapy. To better understand the mechanisms in which ERβ can modulate breast cancer therapies, we introduced ERβ under an inducible promoter into MCF-7 breast cancer cells. In these cells, induction of ERβ expression led to a shift in the potency and an increase in the efficacy of tamoxifen to inhibit proliferation. A similar effect on breast cancer cells was observed for two other antiestrogens, raloxifene, and fulvestrant. Induced expression of ERβ did not enhance the antiproliferative effects of small molecule inhibitors that target the epidermal growth factor receptor, insulin growth factor receptor-1 and histone deacetylase, indicating ERβ specifically cooperates with antiestrogens. The combination of ERβ expression, which arrests cells in G2, and tamoxifen, which arrests cells in G1, led to a potent blockade of the cell cycle. ERβ also increased tamoxifen-induced cell death and cooperated with tamoxifen to induce expression of the pro-apoptotic gene bik. In summary, our data indicates that ERβ increases the efficacy of antiestrogens by effects on apoptosis and on cell cycling and, together with clinical observations, suggests ERβ could be a valuable prognostic marker and potential therapeutic target.


Estrogen receptor beta Breast cancer Tamoxifen Fulvestrant Raloxifene Antiestrogens 



We would particularly like to thank Paul Webb for carefully reading and providing helpful suggestions regarding this manuscript. We would also like to thank Fred Schaufele, Marianna Zavodoskaya, and Ira Goldfine for helpful discussions. Financial support was provided by the National Cancer Institute, NIH R01 CA 80210 (PJK) and the California Breast Cancer Research Project, 10FB-0046 (LHG). Peter Kushner has significant financial interests in, and is a former Director and Consultant to, Karobio AB a biotech company that develops ligands for nuclear receptors.


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Leslie Hodges-Gallagher
    • 1
    • 2
  • Cathleen D. Valentine
    • 1
  • Suzy El Bader
    • 1
  • Peter J. Kushner
    • 1
  1. 1.Department of MedicineUniversity of CaliforniaSan FranciscoUSA
  2. 2.Combithera Inc.San FranciscoUSA

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