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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis

Rui-Hong Wang1, Yin Zheng, Hyun-Seok Kim

  • 1Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.

Molecular Cell
|October 15, 2008
PubMed

Insights

BRCA1 mutations increase breast and ovarian cancer risk. This study reveals SIRT1

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Germline mutations in BRCA1 are linked to hereditary breast and ovarian cancers.
  • The precise mechanisms of BRCA1 tumor suppression are not fully understood.
  • Downstream targets of BRCA1 in cancer prevention require further elucidation.

Purpose of the Study:

  • To investigate the role of SIRT1 in BRCA1-associated tumorigenesis.
  • To explore the therapeutic potential of targeting SIRT1 and Survivin in BRCA1-mutant cancers.

Main Methods:

  • Analysis of SIRT1 and Survivin levels in human BRCA1-associated breast cancers and Brca1 mutant mouse models.
  • Investigating BRCA1's interaction with the SIRT1 promoter and its effect on gene expression.
  • Assessing the impact of resveratrol on Sirt1 activation and Survivin inhibition in vitro and in vivo.

Main Results:

  • BRCA1-associated cancers exhibit reduced SIRT1 and elevated Survivin levels.
  • BRCA1 directly upregulates SIRT1 expression, which epigenetically suppresses Survivin.
  • Resveratrol demonstrates enhanced efficacy against Brca1 mutant cancer cells by activating Sirt1 and inhibiting Survivin.

Conclusions:

  • SIRT1 is a key mediator of BRCA1's tumor suppressor function.
  • The SIRT1-Survivin axis is critical in BRCA1-associated cancers.
  • Resveratrol represents a promising targeted therapy for BRCA1-associated breast cancer.

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