Abstract 5090: Estrogen receptor-alpha promotes multi-centrosomes by inhibition of BRCA1-Rad51 binding

Abstract

Abstract Von Hippel Lindau gene (VHL) is frequently deleted in renal cell carcinoma and known to be negative regulator of Hypoxia inducible factor-1 (HIF-1). However, its tumor suppressive functions has not been fully explained by HIF-1 suppression, because loss of pVHL is appeared in initial stage of RCC tumorigenesis and induces the defect in cytokinesis or centrosome instability. Concerning this, we previously revealed that estrogen receptor-alpha is primary target of E3 ligase function of pVHL. In this study, we demonstrate that ER-α is responsible for mitotic defect and drug resistance in VHL-deficient cells. Activated ER-α can interact with BRCA1 or Rad51 and disrupt the BRCA1-Rad51-mediated centrosome maintaining. Thus, VHL-deficient cells, like as BRCA1-deficient cells, possessed multi-centrosome and multi-nucleated phenotypes. In addition, multi-centrosomal features rendered the resistance to Taxol. Since it is mediated by ER-α in nucleus, blocking of ER-α translocation by specific inhibitor, Faslodex, can ameliorate multi-centrosomes and induce Taxol sensitivity in RCC and BRCA1-deficient breast cancers. These results suggest that pVHL is critical for proper cell division and suppression of ER-α in RCC and BRCA1-deficient breast cancer is one of useful strategy for improving the drug sensitivity. Citation Format: Youn-Sang Jung, Ho-Young Chun, Tae-Gyun Woo, Bum-Joon Park. Estrogen receptor-alpha promotes multi-centrosomes by inhibition of BRCA1-Rad51 binding. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5090. doi:10.1158/1538-7445.AM2014-5090