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Article: BRCA1 deficiency induces protective autophagy to mitigate stress and provides a mechanism for BRCA1 haploinsufficiency in tumorigenesis

TitleBRCA1 deficiency induces protective autophagy to mitigate stress and provides a mechanism for BRCA1 haploinsufficiency in tumorigenesis
Authors
Issue Date2014
PublisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/canlet
Citation
Cancer Letters, 2014, v. 346 n. 1, p. 139-147 How to Cite?
AbstractStress 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.
Persistent Identifierhttp://hdl.handle.net/10722/194758
ISSN
2015 Impact Factor: 5.992
2015 SCImago Journal Rankings: 2.331
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTang, MKSen_US
dc.contributor.authorKwong, Aen_US
dc.contributor.authorTam, KFen_US
dc.contributor.authorCheung, ANYen_US
dc.contributor.authorNgan, HYSen_US
dc.contributor.authorXia, Wen_US
dc.contributor.authorWong, ASTen_US
dc.date.accessioned2014-02-17T02:07:00Z-
dc.date.available2014-02-17T02:07:00Z-
dc.date.issued2014-
dc.identifier.citationCancer Letters, 2014, v. 346 n. 1, p. 139-147en_US
dc.identifier.issn0304-3835-
dc.identifier.urihttp://hdl.handle.net/10722/194758-
dc.description.abstractStress 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.-
dc.languageengen_US
dc.publisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/canlet-
dc.relation.ispartofCancer Lettersen_US
dc.titleBRCA1 deficiency induces protective autophagy to mitigate stress and provides a mechanism for BRCA1 haploinsufficiency in tumorigenesisen_US
dc.typeArticleen_US
dc.identifier.emailTang, MKS: maggieks@hku.hken_US
dc.identifier.emailKwong, A: avakwong@hkucc.hku.hken_US
dc.identifier.emailTam, KF: tamkf@hkucc.hku.hken_US
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_US
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_US
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_US
dc.identifier.authorityKwong, A=rp01734en_US
dc.identifier.authorityCheung, ANY=rp00542en_US
dc.identifier.authorityNgan, HYS=rp00346en_US
dc.identifier.authorityWong, AST=rp00805en_US
dc.identifier.doi10.1016/j.canlet.2013.12.026-
dc.identifier.pmid24378767-
dc.identifier.hkuros227657en_US
dc.identifier.hkuros233698-
dc.identifier.volume346-
dc.identifier.issue1-
dc.identifier.spage139-
dc.identifier.epage147-
dc.identifier.isiWOS:000334017000016-
dc.publisher.placeIreland-

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