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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / pharmacology
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BRCA1 Protein / metabolism
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Epigenesis, Genetic
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Female
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Genes, BRCA1*
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Germ-Line Mutation
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Humans
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Inhibitor of Apoptosis Proteins
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / genetics*
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Mammary Neoplasms, Experimental / metabolism*
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Mice
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Mice, Mutant Strains
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Mice, Nude
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Mice, Transgenic
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Microtubule-Associated Proteins / antagonists & inhibitors
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Microtubule-Associated Proteins / genetics*
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Microtubule-Associated Proteins / metabolism*
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Neoplasm Proteins / metabolism
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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RNA Interference
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Repressor Proteins
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Resveratrol
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Sirtuin 1
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Sirtuins / genetics*
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Sirtuins / metabolism*
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Stilbenes / pharmacology
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Survivin
Substances
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Antineoplastic Agents, Phytogenic
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BIRC5 protein, human
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BRCA1 Protein
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Birc5 protein, mouse
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Repressor Proteins
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Stilbenes
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Survivin
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SIRT1 protein, human
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Sirt1 protein, mouse
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Sirtuin 1
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Sirtuins
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Resveratrol