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The molecular mechanisms underlying the ER?-36-mediated signaling in breast cancer.


ABSTRACT: 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 (ER?-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 ER?-negative cell line and in an original patient-derived xenograft. After estrogen treatment, ER?-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 ER?-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 ER?-36-positive patients.

SUBMITTER: Omarjee S 

PROVIDER: S-EPMC5422711 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

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

Oncogene 20161212 18


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 xenogr  ...[more]

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