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.

Nrf2 facilitates repair of radiation induced DNA damage through homologous recombination repair pathway in a ROS independent manner in cancer cells

“…Another gene which was shown to have ARE sequence in the BLAST analysis, RBBP8, has been reported to interact with BRCA1, a crucial protein involved in DSB repair and recombination. A recent study [35] has also reported the direct interaction of BRCA1 with Nrf2, in execution of cell survival functions. It would also be interesting to extend this study in normal cells, where the role of Nrf2 in DNA repair will have implication in radioprotection.…”

Role of the Nrf2 signaling system in health and disease

“…1. (11,(22)(23)(24)(25)(26), and binding of competing proteins to Keap1 allowing increased activity of Nrf2 (27,28). Several mechanisms participate in the regulation of Nrf2 activity.…”

Redox homeostasis of breast cancer lineages contributes to differential cell death response to exogenous hydrogen peroxide

“…Importantly, new insights have placed ROS as a key-factor in BRCA1-related breast cancers etiology due to BRCA1-NRF2 interaction and influence on NRF2-dependent antioxidant ability [24].…”