Journal Article

The molecular mechanisms underlying the ERα-36-mediated signaling in breast cancer

Romancer, M Le, Omarjee, S, Treilleux, I, Jacquemetton, J, Poulard, C, Corbo, L, Dejaegere, A, Chebaro, Y, Marangoni, E, Rochel, N

2017

Overview

Alterations in estrogen-mediated cellular signaling have largely been implicated in the pathogenesis of breast cancer. Here, we investigated the signaling regulation of a splice variant of the estrogen receptor, namely estrogen receptor (ERα-36), associated with a poor prognosis in breast cancers. Coupling in vitro and in vivo approaches we determined the precise sequential molecular events of a new estrogen signaling network in an ERα-negative cell line and in an original patient-derived xenograft. After estrogen treatment, ERα-36 rapidly associates with Src at the level of the plasma membrane, initiating downstream cascades, including MEK1/ERK activation and paxillin phosphorylation on S126, which in turn triggers a higher expression of cyclin D1. Of note, the direct binding of ERα-36 to ERK2 prevents its dephosphorylation by MKP3 and enhances the downstream signaling. These findings improve our understanding of the regulation of non-genomic estrogen signaling and open new avenues for personalized therapeutic approaches targeting Src or MEK in ERα-36-positive patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1347 / 631/80/86/2363 / 82 / 96/1 / 96/109 / 96/95 / Animals / Apoptosis / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cell Biology / Estrogen Receptor alpha - biosynthesis / Estrogen Receptor alpha - genetics / Female / Human Genetics / Humans / Internal Medicine / MAP Kinase Kinase 1 - genetics / MCF-7 Cells / Medicine / Medicine & Public Health / Mice / Oncogene Protein pp60(v-src) - genetics / Oncology / Original / original-article / Protein Isoforms - biosynthesis / Protein Isoforms - genetics / Signal Transduction / Xenograft Model Antitumor Assays