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

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. © 2007 Springer Science+Business Media, LLC.