Journal article
Estrogen controls the survival of BRCA1-deficient cells via a PI3K–NRF2-regulated pathway
Proceedings of the National Academy of Sciences - PNAS, Vol.111(12), pp.4472-4477
From the Cover
03/25/2014
Handle:
https://hdl.handle.net/2376/100814
PMCID: PMC3970526
PMID: 24567396
Abstract
Our establishment of a connection between the phosphatidylinositol 3-kinase (PI3K) and NRF2 pathways provides the basis for the tissue specificity of BRCA1-related cancers. Because BRCA1 is a vital component of the intracellular machinery maintaining genomic stability, BRCA1 functions as a major tumor suppressor in cells of all types. However, BRCA1-related cancers occur overwhelmingly in breasts and ovaries. Our work demonstrates that estrogen (E2) acts via the PI3K–AKT pathway to regulate NRF2 activation in BRCA1-deficient cells, resulting in the induction of antioxidant genes that protect the cell from reactive oxygen species-induced death. BRCA1-deficient cells are thus allowed to survive and may accumulate mutations, such as loss of PTEN, that perpetuate NRF2 activation. Our work supports the emerging clinical strategy of treating BRCA1-related cancers with PI3K inhibitors.
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.
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Details
- Title
- Estrogen controls the survival of BRCA1-deficient cells via a PI3K–NRF2-regulated pathway
- Creators
- Chiara Gorrini - , Ontario Cancer Institute, University Health Network, Toronto, ONBevan P Gang - , Ontario Cancer Institute, University Health Network, Toronto, ONChristian Bassi - Department of Medical BiophysicsAndrew Wakeham - , Ontario Cancer Institute, University Health Network, Toronto, ONShakiba Pegah Baniasadi - , Ontario Cancer Institute, University Health Network, Toronto, ONZhenyue Hao - , Ontario Cancer Institute, University Health Network, Toronto, ONWanda Y Li - , Ontario Cancer Institute, University Health Network, Toronto, ONDavid W Cescon - , Ontario Cancer Institute, University Health Network, Toronto, ONYen-Ting Li - , Ontario Cancer Institute, University Health Network, Toronto, ONSam Molyneux - , University Health Network, Toronto, ONNadia Penrod - , Toronto, ONMathieu Lupien - , Toronto, ONEdward E Schmidt - Veterinary Molecular BiologyVuk Stambolic - Department of Medical BiophysicsMona L Gauthier - , Ontario Cancer Institute, University Health Network, Toronto, ONTak W Mak - , Ontario Cancer Institute, University Health Network, Toronto, ON
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.111(12), pp.4472-4477
- Academic Unit
- Biomedical Sciences, Department of
- Series
- From the Cover
- Publisher
- National Academy of Sciences
- Identifiers
- 99900546656901842
- Language
- English
- Resource Type
- Journal article