title: NF-κB is a critical mediator of BRCA1-induced chemoresistance.
abstract: BRCA1 mediates resistance to apoptosis in response to DNA-damaging agents, causing BRCA1 wild-type tumours to be significantly more resistant to DNA damage than their mutant counterparts. In this study, we demonstrate that following treatment with the DNA-damaging agents, etoposide or camptothecin, BRCA1 is required for the activation of nuclear factor-κB (NF-κB), and that BRCA1 and NF-κB cooperate to regulate the expression of the NF-κB antiapoptotic targets BCL2 and XIAP. We show that BRCA1 and the NF-κB subunit p65/RelA associate constitutively, whereas the p50 NF-κB subunit associates with BRCA1 only upon DNA damage treatment. Consistent with this BRCA1 and p65 are present constitutively on the promoters of BCL2 and XIAP, whereas p50 is recruited to these promoters only in damage treated cells. Importantly, we demonstrate that the recruitment of p50 onto the promoters of BCL2 and XIAP is dependent upon BRCA1, but independent of its NF-κB partner subunit p65. The functional relevance of NF-κB activation by BRCA1 in response to etoposide and camptothecin is demonstrated by the significantly reduced survival of BRCA1 wild-type cells upon NF-κB inhibition. This study identifies a novel BRCA1-p50 complex, and demonstrates for the first time that NF-κB is required for BRCA1-mediated resistance to DNA damage. It reveals a functional interdependence between BRCA1 and NF-κB, further elucidating the role played by NF-κB in mediating cellular resistance of BRCA1 wild-type tumours to DNA-damaging agents.
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: Mary T
authors: MT
authors: Harte
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: Julia J
authors: JJ
authors: Gorski
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: Kienan I
authors: KI
authors: Savage
authors: James W
authors: JW
authors: Purcell
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: Eliana M
authors: EM
authors: Barros
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: Philip M
authors: PM
authors: Burn
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: Cheryl
authors: C
authors: McFarlane
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: Paul B
authors: PB
authors: Mullan
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: Richard D
authors: RD
authors: Kennedy
authors: Neil D
authors: ND
authors: Perkins
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK BT9 7BL.
authors: D Paul
authors: DP
authors: Harkin
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D005047:Etoposide; D002166:Camptothecin