BRCA1 Induces Antioxidant Gene Expression and Resistance to Oxidative Stress

Abstract

Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor, confer an increased risk for breast, ovarian, and prostate cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to identify BRCA1-regulated gene expression changes. We found that BRCA1 up-regulates the expression of multiple genes involved in the cytoprotective antioxidant response, including glutathione S-transferases, oxidoreductases, and other antioxidant genes. Consistent with these findings, BRCA1 overexpression conferred resistance while BRCA1 deficiency conferred sensitivity to several different oxidizing agents (hydrogen peroxide and paraquat). In addition, in the setting of oxidative stress (due to hydrogen peroxide), BRCA1 shifted the cellular redox balance to a higher ratio of reduced to oxidized glutathione. Finally, BRCA1 stimulated antioxidant response element-driven transcriptional activity and enhanced the activity of the antioxidant response transcription factor nuclear factor erythroid-derived 2 like 2 [also called NRF2 (NFE2L2)]. The ability of BRCA1 to stimulate antioxidant response element-dependent transcription and to protect cells against oxidative stress was attenuated by inhibition of nuclear factor erythroid-derived 2 like 2. These findings suggest a novel function for BRCA1, i.e., to protect cells against oxidative stress. This function would be consistent with the postulated role of BRCA1 as a caretaker gene in preserving genomic integrity.

Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers

“…More importantly, BRCA1 upregulates the expression of genes involved in antioxidant response, including GST genes (Bae et al, 2004). In accordance, BRCA1 deficiency conferred sensitivity to several oxidising agents in cell lines (Bae et al, 2004).…”

“…More importantly, BRCA1 upregulates the expression of genes involved in antioxidant response, including GST genes (Bae et al, 2004). In accordance, BRCA1 deficiency conferred sensitivity to several oxidising agents in cell lines (Bae et al, 2004). The lack of effect in BRCA1 carriers could be related to the already high oxidative stress in cells deficient in the BRCA1 protein; the addition of low active GSTP1 does not significantly add to the process of tumorigenesis.…”

Cancer, Oxidative Stress, and Metastasis

“…Loss-of-function mutations in multiple tumor suppressors that promote genomic integrity, including ataxia telangiectasia mutated (ATM), P53, and BRCA1, lead to the generation of ROS (Bae et al 2004;Reliene et al 2004;Sablina et al 2005;Reliene and Schiestl 2006;Esteve et al 2010;Gorrini et al 2013a). This may reflect the leakage of damaged DNA into the cytoplasm in these cells, inducing an interferon-mediated innate immune response (as would be stimulated by viral DNA) that promotes the generation of ROS (Santos et al 2014;Tasdogan et al 2016;A Tasdogan and H Fehling, pers.…”

BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

“…However, new functions of BRCA1 such as the regulation of the oncogenic microRNA 155 (Chang et al, 2011), the maintenance of heterochromatin structure (Zhu et al, 2011), and the modulation of oxidative stress (Vurusaner et al, 2012) have been recently discovered. In the context of oxidative stress, BRCA1 overexpression in human breast cancer cells up-regulates several antioxidant genes and reduces H 2 O 2 -induced DNA damage and apoptosis (Bae et al, 2004;Saha et al, 2009). Although Brca1 loss-of-function in mouse embryonic fibroblasts from Brca1 11/11 mutant mice shows higher ROS levels than cells from Brca1 WT mice and is more sensitive to apoptosis induced by oxidative stress (Cao et al, 2007), the mechanism by which BRCA1 regulates oxidative stress and its impact in BRCA1-associated tumorigenesis has not been fully uncovered.…”