Interplay Among BRCA1, SIRT1, and Survivin During BRCA1-associated Tumorigenesis

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2008 Oct 15

PMID 18851829

Citations 191

Authors

Rui-Hong Wang

Yin Zheng

Hyun-Seok Kim

Xiaoling Xu

Liu Cao

Tyler Luhasen

Mi-Hye Lee

Cuiying Xiao

Athanassios Vassilopoulos

Weiping Chen

Kevin Gardner

Yan-Gao Man

Mien-Chie Hung

Toren Finkel

Chu-Xia Deng

Affiliations

Soon will be listed here.

Abstract

Germline mutations of BRCA1 predispose women to breast and ovarian cancers. However, the downstream mediators of BRCA1 function in tumor suppression remain elusive. We found that human BRCA1-associated breast cancers have lower levels of SIRT1 than their normal controls. We further demonstrated that mammary tumors from Brca1 mutant mice have low levels of Sirt1 and high levels of Survivin, which is reversed by induced expression of Brca1. BRCA1 binds to the SIRT1 promoter and increases SIRT1 expression, which in turn inhibits Survivin by changing the epigenetic modification of histone H3. Absence of SIRT1 blocks the regulation of Survivin by BRCA1. Furthermore, we demonstrated that activation of Sirt1 and inhibition of Survivin expression by resveratrol elicit a more profound inhibitory effect on Brca1 mutant cancer cells than on Brca1-wild-type cancer cells both in vitro and in vivo. These findings suggest that resveratrol treatment serves as an excellent strategy for targeted therapy for BRCA1-associated breast cancer.

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