title: The molecular mechanisms underlying the ERα-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 (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.
authors.affiliation: Université Lyon 1, Lyon, France.|INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Omarjee
authors.affiliation: Université Lyon 1, Lyon, France.|INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: J
authors.initials: J
authors.lastname: Jacquemetton
authors.affiliation: Université Lyon 1, Lyon, France.|INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Poulard
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|CNRS UMR7104, Illkirch, France.|INSERM U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: N
authors.initials: N
authors.lastname: Rochel
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|CNRS UMR7104, Illkirch, France.|INSERM U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: A
authors.initials: A
authors.lastname: Dejaegere
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|CNRS UMR7104, Illkirch, France.|INSERM U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Chebaro
authors.affiliation: Université Lyon 1, Lyon, France.|INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Centre Léon Bérard, Pathology Department, Lyon, France.
authors.forename: I
authors.initials: I
authors.lastname: Treilleux
authors.affiliation: Institut Curie, Translational Research Department, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Université Lyon 1, Lyon, France.|INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: L
authors.initials: L
authors.lastname: Corbo
authors.affiliation: Université Lyon 1, Lyon, France.|INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: M Le
authors.initials: ML
authors.lastname: Romancer
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D061986:MCF-7 Cells; D051379:Mice; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020033:Protein Isoforms; D015688:Oncogene Protein pp60(v-src); D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human