ER-α36, a Variant of ER-α, Promotes Tamoxifen Agonist Action in Endometrial Cancer Cells via the MAPK/ERK and PI3K/Akt Pathways

Abstract

BACKGROUND: Recently, a novel variant of ER-alpha, ER-alpha36 was identified and cloned. ER-alpha36 lacks intrinsic transcription activity and mainly mediates nongenomic estrogen signaling. Here, we studied the role of nongenomic estrogen signaling pathways mediated by ER-alpha36 in tamoxifen resistance and agonist action. METHODOLOGY: The cellular localization of ER-alpha36 was examined by immunofluorescence in MCF-7 cells and Hec1A cells. MCF-7 breast cancer cells, MCF-7 cells expressing recombinant ER-alpha36 (MCF-7/ER36), Hec1A endometrial cancer cells and Hec1A cells with siRNA knockdown of ER-alpha36 (Hec1A/RNAiER36) were treated with 17beta-estradial (E2) and tamoxifen (TAM) in the absence and presence of kinase inhibitor U0126 and LY294002. We examined phosphorylation of signaling molecules and the expression of c-Myc by immunoblotting, and tumor cell growth by MTT assay. CONCLUSIONS: ER variant ER-alpha36 enhances TAM agonist activity through activation of the membrane-initiated signaling pathways in endometrial cancer, and that ER-alpha36 is involved in de novo and acquired TAM resistance in breast cancer.