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首页> 外文期刊>Oncogene >The molecular mechanisms underlying the ER|[alpha]|-36-mediated signaling in breast cancer
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The molecular mechanisms underlying the ER|[alpha]|-36-mediated signaling in breast cancer

机译：乳腺癌中ER |α| -36介导信号转导的分子机制

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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.
机译：雌激素介导的细胞信号转导的改变主要与乳腺癌的发病机理有关。在这里，我们调查了雌激素受体剪接变异体，即雌激素受体（ERα-36）的信号传导调控，与乳腺癌的不良预后相关。在体外和体内的耦合方法中，我们确定了新的雌激素信号网络在ERα阴性细胞系和原始患者衍生异种移植物中的精确顺序分子事件。雌激素处理后，ERα-36在质膜水平上与Src迅速缔合，引发下游级联反应，包括MEK1 / ERK激活和S126上的paxillin磷酸化，进而触发细胞周期蛋白D1的更高表达。值得注意的是，ERα-36与ERK2的直接结合可防止其被MKP3去磷酸化并增强下游信号传导。这些发现改善了我们对非基因组雌激素信号传导调控的理解，并为针对ERα-36阳性患者的Src或MEK的个性化治疗方法开辟了新途径。

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