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

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Abstract

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.

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Acknowledgments

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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  1. Leslie Hodges-Gallagher

    Present address: Combithera Inc., 665 Third Street, suite 250, San Francisco, CA, 94107, USA

Authors and Affiliations

  1. Department of Medicine, University of California, Box 1640, San Francisco, CA, 94143, USA

    Leslie Hodges-Gallagher, Cathleen D. Valentine, Suzy El Bader & Peter J. Kushner

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  1. Leslie Hodges-Gallagher
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Correspondence to Peter J. Kushner.

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Hodges-Gallagher, L., Valentine, C.D., Bader, S.E. et al. Estrogen receptor beta increases the efficacy of antiestrogens by effects on apoptosis and cell cycling in breast cancer cells. Breast Cancer Res Treat 109, 241–250 (2008). https://doi.org/10.1007/s10549-007-9640-6

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  • DOI: https://doi.org/10.1007/s10549-007-9640-6

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