Gorrini C, Baniasadi PS, Harris IS, Silvester J, Inoue S, Snow B, Joshi PA, Wakeham A, Molyneux SD, Martin B, Bouwman P, Cescon DW, Elia AJ, Winterton-Perks Z, Cruickshank J, Brenner D, Tseng A, Musgrave M, Berman HK, Khokha R, Jonkers J, Mak TW, Gauthier ML

The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario M5G 2M9, Canada.

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.

Mesh Terms:
Animals, Antioxidants, BRCA1 Protein, Breast Neoplasms, Cell Line, Cell Survival, Cell Transformation, Neoplastic, Epithelial Cells, Estrogens, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Mammary Glands, Animal, Mice, Mutation, NAD(P)H Dehydrogenase (Quinone), NF-E2-Related Factor 2, Oxidative Stress, Protein Binding, Protein Stability, Reactive Oxygen Species, Signal Transduction, Ubiquitination

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