Brca1 deficiency exacerbates estrogen-induced dna damage and genomic instability

Kienan I. Savage, Kyle B. Matchett, Eliana M. Barros, Kevin M. Cooper, Gareth W. Irwin, Julia J. Gorski, Katy S. Orr, Jekaterina Vohhodina, Joy N. Kavanagh, Angelina F. Madden, Alexander Powell, Lorenzo Manti, Simon S. Mcdade, Ben Ho Park, Kevin M. Prise, Stuart A. Mcintosh, Manuel Salto-Tellez, Derek J. Richard, Christopher T. Elliott, D. Paul Harkin

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptora- negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability.We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

Original languageEnglish (US)
Pages (from-to)2773-2784
Number of pages12
JournalCancer Research
Issue number10
StatePublished - May 15 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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