title: BRCA1 deficiency induces protective autophagy to mitigate stress and provides a mechanism for BRCA1 haploinsufficiency in tumorigenesis.
abstract: Stress adaptation has profound impacts on malignant progression and response to treatment. BRCA1 is an important modulator of cellular stress, but our understanding of its mechanisms of action remains incomplete. Here we identify autophagy as an essential mechanism protecting BRCA1 deficient cancer cells from metabolic stress and allow their survival, which may underlie its significant cancer-promoting properties. We showed that targeted inhibition of endogenous BRCA1 using small interfering RNA caused significant autophagy in response to serum starvation and endoplasmic reticulum stress, whereas overexpression of BRCA1 did not, confirming that the effect was BRCA1 specific. We demonstrated that Beclin 1 was activated in BRCA1 deficient cells, suggesting involvement of a canonical pathway. Importantly, BRCA1 deficient cells were highly dependent on autophagy for survival, and rapidly underwent cell death upon disruption of autophagy. Notably, this dependence on protective autophagy extended to their tissue of origin, as ovarian surface epithelial cells from women testing positive for BRCA1 mutations, in contrast to those with no mutations, robustly induced autophagy to mitigate the stress and promote their survival. These findings highlight a novel role for BRCA1 in protective autophagy, which may make its essential contribution to tumorigenesis and prognosis.
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Maggie K S
authors.initials: MK
authors.lastname: Tang
authors.affiliation: Department of Surgery, University of Hong Kong, Pokfulam Road, Hong Kong; Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong.
authors.forename: Ava
authors.initials: A
authors.lastname: Kwong
authors.affiliation: Department of Obstetrics and Gynecology, University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Kar-Fai
authors.initials: KF
authors.lastname: Tam
authors.affiliation: Department of Pathology, University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Annie N Y
authors.initials: AN
authors.lastname: Cheung
authors.affiliation: Department of Obstetrics and Gynecology, University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Hextan Y S
authors.initials: HY
authors.lastname: Ngan
authors.affiliation: School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China; Clinical Stem Cell Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Xia
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong. Electronic address: awong1@hku.hk.
authors.forename: Alice S T
authors.initials: AS
authors.lastname: Wong
mesh_terms: D001343:Autophagy / Q000235:genetics*; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D047468:Immunoprecipitation; D046529:Microscopy, Electron, Transmission; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D014162:Transfection
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D034741:RNA, Small Interfering
keywords: Autophagy; BRCA1; Breast cancer; Ovarian cancer; Survival