BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

Chiara Gorrini, Pegah S. Baniasadi, Isaac S. Harris, Jennifer Silvester, Satoshi Inoue, Bryan Snow, Purna A. Joshi, Andrew Wakeham, Sam D. Molyneux, Bernard Martin, Peter Bouwman, David W. Cescon, Andrew J. Elia, Zoe Winterton-Perks, Jennifer Cruickshank, Dirk Brenner, Alan Tseng, Melinda Musgrave, Hal K. Berman, Rama KhokhaJos Jonkers, Tak W. Mak*, Mona L. Gauthier

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

218 Citations (Scopus)

Abstract

Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.

Original languageEnglish
Pages (from-to)1529-1544
Number of pages16
JournalJournal of Experimental Medicine
Volume210
Issue number8
DOIs
Publication statusPublished - 2013
Externally publishedYes

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