title: BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival.
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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gorrini
authors.forename: Pegah S
authors.initials: PS
authors.lastname: Baniasadi
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Harris
authors.forename: Jennifer
authors.initials: J
authors.lastname: Silvester
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Bryan
authors.initials: B
authors.lastname: Snow
authors.forename: Purna A
authors.initials: PA
authors.lastname: Joshi
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Sam D
authors.initials: SD
authors.lastname: Molyneux
authors.forename: Bernard
authors.initials: B
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.forename: David W
authors.initials: DW
authors.lastname: Cescon
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Elia
authors.forename: Zoe
authors.initials: Z
authors.lastname: Winterton-Perks
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cruickshank
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.forename: Alan
authors.initials: A
authors.lastname: Tseng
authors.forename: Melinda
authors.initials: M
authors.lastname: Musgrave
authors.forename: Hal K
authors.initials: HK
authors.lastname: Berman
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Mona L
authors.initials: ML
authors.lastname: Gauthier
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011485:Protein Binding; D055550:Protein Stability; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D000975:Antioxidants; D019313:BRCA1 Protein; D004967:Estrogens; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human