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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Hao, Zhenyue Schmidt, Edward E. Wakeham, Andrew Cescon, David W. Lupien, Mathieu Bassi, Christian Baniasadi, Shakiba Pegah Penrod, Nadia Gauthier, Mona L. Li, Yen-ting Gang, Bevan P. Stambolic, Vuk Mak, Tak W. Li, Wanda Y. Molyneux, Sam Gorrini, Chiara |
| Description | Author Affiliation: Gorrini C ( The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.); |
| Abstract | 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 12 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | BRCA1 Protein Genetics Cell Survival Physiology Estrogens NF-E2-Related Factor 2 Metabolism Phosphatidylinositol 3-Kinases Animals Heterografts Mice Mice, Transgenic Oxidative Stress Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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