Journal Article

Estrogen controls the survival of BRCA1-deficient cells via a PI3K–NRF2-regulated pathway

Hao, Zhenyue, Schmidt, Edward E., Wakeham, Andrew, Li, Yen-Ting, Cescon, David W., Lupien, Mathieu, Bassi, Christian, Baniasadi, Shakiba Pegah, Penrod, Nadia, Gauthier, Mona L., Gang, Bevan P., Stambolic, Vuk, Mak, Tak W., Li, Wanda Y., Molyneux, Sam, Gorrini, Chiara

2014

Overview

Mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. The mechanism underlying the tissue-specific nature of BRCA1's tumor suppression is obscure. We previously showed that the antioxidant pathway regulated by the transcription factor NRF2 is defective in BRCA1-deficient cells. Reactivation of NRF2 through silencing of its negative regulator KEAP1 permitted the survival of BRCA1-null cells. Here we show that estrogen (E2) increases the expression of NRF2-dependent antioxidant genes in various E2-responsive cell types. Like NRF2 accumulation triggered by oxidative stress, E2-induced NRF2 accumulation depends on phosphatidylinositol 3-kinase–AKT activation. Pretreatment of mammary epithelial cells (MECs) with the phosphatidylinositol 3-kinase inhibitor BKM120 abolishes the capacity of E2 to increase NRF2 protein and transcriptional activity. In vivo the survival defect of BRCA1-deficient MECs is rescued by the rise in E2 levels associated with pregnancy. Furthermore, exogenous E2 administration stimulates the growth of BRCA1-deficient mammary tumors in the fat pads of male mice. Our work elucidates the basis of the tissue specificity of BRCA1-related tumor predisposition, and explains why oophorectomy significantly reduces breast cancer risk and recurrence in women carrying BRCA1 mutations.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Antioxidants / B lymphocytes / Biological Sciences / BRCA1 Protein - genetics / Breast cancer / Cancer / Cell lines / Cell Survival - physiology / Estrogens / Estrogens - physiology / Female / Gene expression regulation / Genes / Genetic mutation / Health risks / Heterografts / Hormones / Mice / Mice, Transgenic / Mutation / NF-E2-Related Factor 2 - metabolism / Oxidative Stress / Phosphatidylinositol 3-Kinases - metabolism / Risk factors / Tumors