title: The role of calcium in the activation of estrogen receptor-alpha.
abstract: Environmental estrogen mimics, including metalloestrogens that can activate estrogen receptor-alpha (ERα), may contribute to breast cancer risk. However, the underlying mechanisms through which these molecular mimics activate the ERα 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 ERα and the ligand-binding domain of ERα. MCF-7 cells treated with EGF, ATP, extracellular calcium, or caffeine to increase intracellular calcium triggered a rapid recruitment of ERα 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 ERα and the activation was blocked by the antiestrogen. Mechanistic investigations identified four potential sites on the solvent-accessible surface of the ERα ligand-binding domain as important for calcium activation of the receptor. Taken together, our results suggest that calcium mediates the cross-talk between ERα-activating signaling pathways and the ligand-binding domain of ERα providing a potential explanation for the ability of certain environmental metalloestrogens to activate the receptor.
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Shailaja D
authors.initials: SD
authors.lastname: Divekar
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Storchan
authors.forename: Katherine
authors.initials: K
authors.lastname: Sperle
authors.forename: David J
authors.initials: DJ
authors.lastname: Veselik
authors.forename: Earl
authors.initials: E
authors.lastname: Johnson
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Yuse N
authors.initials: YN
authors.lastname: Lajiminmuhip
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Nakles
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Martin
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D020239:Receptor Cross-Talk / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D047628:Estrogen Receptor alpha; D002118:Calcium