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Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155.

BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors.

Pubmed ID: 21946536


  • Chang S
  • Wang RH
  • Akagi K
  • Kim KA
  • Martin BK
  • Cavallone L
  • Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)
  • Haines DC
  • Basik M
  • Mai P
  • Poggi E
  • Isaacs C
  • Looi LM
  • Mun KS
  • Greene MH
  • Byers SW
  • Teo SH
  • Deng CX
  • Sharan SK


Nature medicine

Publication Data

October 12, 2011

Associated Grants

  • Agency: Intramural NIH HHS, Id: ZIA BC010387-13
  • Agency: Intramural NIH HHS, Id: ZIA BC011181-04

Mesh Terms

  • Analysis of Variance
  • BRCA1 Protein
  • Blotting, Southern
  • Chromatin Immunoprecipitation
  • DNA Repair
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylase 2
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Hybridization
  • MicroRNAs
  • Microarray Analysis
  • Mutation, Missense
  • Reverse Transcriptase Polymerase Chain Reaction