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首页> 外文期刊>Neoplasia: an international journal for oncology research >Elevated Estrogen Receptor-α in VHL-Deficient Condition Induces Microtubule Organizing Center Amplification via Disruption of BRCA1/Rad51 Interaction
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Elevated Estrogen Receptor-α in VHL-Deficient Condition Induces Microtubule Organizing Center Amplification via Disruption of BRCA1/Rad51 Interaction

机译：VHL缺陷条件下的雌激素受体-α升高诱导微管组织中心扩增通过BRCA1 / RAD51相互作用的破坏

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Since loss of VHL is frequently detected early phase genetic event in human renal cell carcinoma, pVHL is assumed to be indispensable for suppression of tumor initiation step. However, induction of HIF-1α, target of pVHL E3 ligase, is more adequate to angiogenesis step after tumor mass formation. Concerning this, it has been reported that pVHL is involved in centrosome location during metaphase and regulates ER-α signaling. Here, we provide the evidences that pVHL-mediated ER-α suppression is critical for microtubule organizing center (MTOC) maintaining and elevated ER-α promotes MTOC amplification through disruption of BRCA1-Rad51 interaction. In fact, numerous MTOC in VHL- or BRCA1-deficient cells are reduced by Fulvestrant, inhibitor of ER-α expression as well as antagonist. In addition, we reveal that activation of ER signaling can increase γ-tubulin, core factor of TuRC and render the resistance to Taxol. Thus, Fulvestrant but not Tamoxifen, antagonist against ER-α, can restore the Taxol sensitivity in VHL- or BRCA1-deficient cells. Our results suggest that pVHL-mediated ER-α suppression is important for regulation of MTOC as well as drug resistance.
机译：由于VHL的丧失经常检测到人类肾细胞癌中的早期遗传事件，假设PVHL对于抑制肿瘤起始步骤是必不可少的。然而，诱导HIF-1α，PVHL E3连接酶的靶标在肿瘤大量形成之后更适用于血管生成步骤。关于这一点，据报道，PVHL在中期期间参与了Centosome位置并调节ER-α信号传导。在这里，我们提供了PVHL介导的ER-α抑制对于微管组织中心（MTOC）保持和升高的ER-α通过破坏BRCA1-RAD51相互作用来促进MTOC扩增的证据。实际上，通过氟斯特朗特，ER-α表达的抑制剂以及拮抗剂的血液抑制剂和拮抗剂减少了众多MTOC。此外，我们揭示了ER信号传导的激活可以增加γ-微管蛋白，土耳其核心因子并使紫杉醇的抵抗力。因此，氟斯特朗特但非毒素，拮抗剂免于ER-α，可以恢复VHL-或BRCA1缺陷细胞中的紫杉醇敏感性。我们的研究结果表明，PVHL介导的ER-α抑制对于MTOC的调节以及耐药性很重要。

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