BRCA1 induces antioxidant gene expression and resistance to oxidative stress.
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.
Bae
Insoo
I
Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057-1469, USA.
Fan
Saijun
S
Meng
Qinghui
Q
Rih
Jeong Keun
JK
Kim
Hee Jong
HJ
Kang
Hyo Jin
HJ
Xu
Jingwen
J
Goldberg
Itzhak D
ID
Jaiswal
Anil K
AK
Rosen
Eliot M
EM
D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D019398:Genes, BRCA1 / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020218:Response Elements / Q000502:physiology; D014158:Transcription, Genetic
D000975:Antioxidants; D005978:Glutathione