title: Estrogen controls the survival of BRCA1-deficient cells via a PI3K-NRF2-regulated pathway.
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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gorrini
authors.forename: Bevan P
authors.initials: BP
authors.lastname: Gang
authors.forename: Christian
authors.initials: C
authors.lastname: Bassi
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Shakiba Pegah
authors.initials: SP
authors.lastname: Baniasadi
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.forename: Wanda Y
authors.initials: WY
authors.lastname: Li
authors.forename: David W
authors.initials: DW
authors.lastname: Cescon
authors.forename: Yen-Ting
authors.initials: YT
authors.lastname: Li
authors.forename: Sam
authors.initials: S
authors.lastname: Molyneux
authors.forename: Nadia
authors.initials: N
authors.lastname: Penrod
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.forename: Edward E
authors.initials: EE
authors.lastname: Schmidt
authors.forename: Vuk
authors.initials: V
authors.lastname: Stambolic
authors.forename: Mona L
authors.initials: ML
authors.lastname: Gauthier
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D002470:Cell Survival / Q000502:physiology*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D064593:Heterografts; D051379:Mice; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D004967:Estrogens; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D019869:Phosphatidylinositol 3-Kinases
keywords: PTEN; breast cancer; hormones; reactive oxygen species