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 HarkinSimon McDade

*Corresponding author for this work

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

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. © 2014 American Association for Cancer Research.

Original languageEnglish
Pages (from-to)2773-2784
Number of pages12
JournalCancer Research
Volume74
Issue number10
Early online date17 Mar 2014
DOIs
Publication statusPublished - 15 May 2014

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