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.
Original language | English |
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Pages (from-to) | 11-20 |
Number of pages | 10 |
Journal | Molecular Cell |
Volume | 32 |
Issue number | 1 |
DOIs | |
State | Published - 10 Oct 2008 |
Bibliographical note
Funding Information:We thank Dr. Zhi-Ming Zheng for critical reading of the manuscript, Dr. Stina Oredsson for the L56Br-C1 cell line, and Dr. Junjie Chen for the HCC1937 and HCC1937-BRCA1-WT cell lines. This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA.
Keywords
- CELLCYCLE
- DNA