Elevated Estrogen Receptor-alpha in VHL-Deficient Condition Induces Microtubule Organizing Center Amplification via Disruption of BRCA1/Rad51 Interaction

Abstract

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-1 alpha, 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-alpha signaling. Here, we provide the evidences that pVHL-mediated ER-alpha suppression is critical for microtubule organizing center (MTOC) maintaining and elevated ER-alpha 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-alpha expression as well as antagonist. In addition, we reveal that activation of ER signaling can increase gamma-tubulin, core factor of TuRC and render the resistance to Taxol. Thus, Fulvestrant but not Tamoxifen, antagonist against ER-alpha, can restore the Taxol sensitivity in VHL-or BRCA1-deficient cells. Our results suggest that pVHL-mediated ER-alpha suppression is important for regulation of MTOC as well as drug resistance.