Regulation of Oxidative Stress Contributes to BRCA1 Tumor Suppression

Antioxidant signaling maintains reactive oxygen species (ROS) homeostasis and has been shown to promote the survival and growth of cancer cells. The expression of antioxidant enzymes is dependent on nuclear factor, erythroid-derived 2-like 2 (NRF2), which is regulated by kelch-like ECH-associated protein 1 (KEAP1)-driven ubiquitination and is often activated by oncogenic signaling. Recent studies have suggested that BRCA1 regulates oxidative stress in breast cancer cells, but how BRCA1 modulates ROS and the role of antioxidant signaling in BRCA1 tumor suppression are poorly understood. Gorrini and colleagues found that Brca1 loss impaired NRF2-mediated activation of antioxidant genes in mouse mammary epithelial cells (MEC) and triggered accumulation of intracellular ROS, resulting in senescence and DNA damage that reduced MEC survival and repopulation potential. In response to oxidative stress, Brca1 expression was increased and promoted antioxidant signaling via induction of Nrf2 transcription. In addition, BRCA1 interacted with NRF2 protein and enhanced its stabilization by disrupting KEAP1-mediated ubiquitination; activation of NRF2 via KEAP1 depletion decreased ROS levels and enhanced the survival of Brca1-deficient MECs. In contrast, knockdown of p53 binding protein 1 (53BP1) rescued cell survival in the absence of Brca1 but did not diminish ROS accumulation. Human BRCA1-mutant breast cancer cells also exhibited impaired NRF2 signaling, including low levels of the NRF2-regulated target NAD(P)H dehydrogenase, quinone 1 and elevated ROS, which increased the sensitivity of these cells to oxidative stress induced by platinum-based chemotherapeutics. Furthermore, estrogen treatment partially rescued NRF2 levels in Brca1-deficient cells, suggesting that estrogen-dependent NRF2 stabilization may counteract oxidative stress and promote the survival of BRCA1-mutant breast and ovarian cells, explaining the tissue specificity of BRCA1-associated tumorigenesis. Together, these findings show that regulation of NRF2 antioxidant signaling is essential for redox homeostasis in the mammary gland and for BRCA1-dependent tumor suppression.

Gorrini C, Baniasadi PS, Harris IS, Silvester J, Inoue S, Snow B, et al. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J Exp Med 2013;210:1529–44.

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