The role of calcium in the activation of estrogen receptor-alpha.

ABSTRACT: Environmental estrogen mimics, including metalloestrogens that can activate estrogen receptor-alpha (ER?), may contribute to breast cancer risk. However, the underlying mechanisms through which these molecular mimics activate the ER? 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 ER? and the ligand-binding domain of ER?. MCF-7 cells treated with EGF, ATP, extracellular calcium, or caffeine to increase intracellular calcium triggered a rapid recruitment of ER? 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 ER? and the activation was blocked by the antiestrogen. Mechanistic investigations identified four potential sites on the solvent-accessible surface of the ER? ligand-binding domain as important for calcium activation of the receptor. Taken together, our results suggest that calcium mediates the cross-talk between ER?-activating signaling pathways and the ligand-binding domain of ER? providing a potential explanation for the ability of certain environmental metalloestrogens to activate the receptor.

SUBMITTER: Divekar SD 

PROVIDER: S-EPMC3057389 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature