Molecular and Cellular Pathobiology The Role of Calcium in the Activation of Estrogen Receptor-Alpha

Environmental estrogen mimics, including metalloestrogens that can activate estrogen receptor-alpha (ERa), may contribute to breast cancer risk. However, the underlying mechanisms through which these molecular mimics activate the ERa are generally poorly understood. With concern to this important question, we investigated whether intracellular calcium may mediate the cross-talk between signaling pathways that activate ERa and the ligand-binding domain of ERa. MCF-7 cells treated with EGF, ATP, extracellular calcium, or caffeine to increase intracellular calcium triggered a rapid recruitment of ERa to estrogen-responsive promoters and stimulated expression of estrogen-responsive genes including pS2, complement C3, and progesterone receptor. Induction was blocked by an antiestrogen but also by the chelation of intracellular calcium. Treatment with extracellular calcium also increased the growth of MCF-7 cells through an ER-dependent mechanism. We found that EGF and extracellular calcium activated the C-terminus of ERa and the activation was blocked by the antiestrogen. Mechanistic investigations identified four potential sites on the solvent-accessible surface of the ERa ligand-binding domain as important for calcium activation of the receptor. Taken together, our results suggest that calciummediates the cross-talk between ERa-activating signaling pathways and the ligand-binding domain of ERa providing a potential explanation for the ability of certain environmental metalloestrogens to activate the receptor. Cancer Res; 71(5); 1–11. 2011 AACR.