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

Clinical evidence indicates that higher levels of estrogen receptor beta (ER beta) predicts improved disease-free and overall survival in patients treated with adjuvant tamoxifen therapy. To better understand the mechanisms in which ERb can modulate breast cancer therapies, we introduced ERb under an inducible promoter into MCF-7 breast cancer cells. In these cells, induction of ERb 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 ERb 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 ERb specifically cooperates with antiestrogens. The combination of ERb expression, which arrests cells in G2, and tamoxifen, which arrests cells in G1, led to a potent blockade of the cell cycle. ERb also increased tamoxifen-induced cell death and cooperated with tamoxifen to induce expression of the proapoptotic gene bik. In summary, our data indicates that ERb increases the efficacy of antiestrogens by effects on apoptosis and on cell cycling and, together with clinical observations, suggests ERb could be a valuable prognostic marker and potential therapeutic target.