Elevated estrogen receptor-α 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-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.

journal_name

Neoplasia

authors

Jung YS,Chun HY,Yoon MH,Park BJ

doi

10.1016/j.neo.2014.09.013

subject

Has Abstract

pub_date

2014-12-01 00:00:00

pages

1070-81

issue

12

eissn

1522-8002

issn

1476-5586

pii

S1476-5586(14)00149-3

journal_volume

16

pub_type

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