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Oncogene. 2017 May 4;36(18):2503-2514. doi: 10.1038/onc.2016.415. Epub 2016 Dec 12.

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

Omarjee S1,2,3, Jacquemetton J1,2,3, Poulard C1,2,3,4, Rochel N5,6,7,8, Dejaegere A5,6,7,8, Chebaro Y5,6,7,8, Treilleux I1,2,3,9, Marangoni E10, Corbo L1,2,3, Romancer ML1,2,3.

Author information

1
Université Lyon 1, Lyon, France.
2
INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
3
CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
4
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
5
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
6
CNRS UMR7104, Illkirch, France.
7
INSERM U964, Illkirch, France.
8
Université de Strasbourg, Illkirch, France.
9
Centre Léon Bérard, Pathology Department, Lyon, France.
10
Institut Curie, Translational Research Department, Paris, France.

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 (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.

PMID:
27941878
PMCID:
PMC5422711
DOI:
10.1038/onc.2016.415
[Indexed for MEDLINE]
Free PMC Article

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