BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability
Data(s) |
15/05/2014
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Resumo |
<p>Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptora- negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability.We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types. © 2014 American Association for Cancer Research.</p> |
Identificador | |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/restrictedAccess |
Fonte |
Savage , K I , Matchett , K B , Barros , E M , Cooper , K M , Irwin , G W , Gorski , J J , Orr , K S , Vohhodina , J , Kavanagh , J N , Madden , A F , Powell , A , Manti , L , McDade , S S , Park , B H , Prise , K M , McIntosh , S A , Salto-Tellez , M , Richard , D J , Elliott , C T & Harkin , D P 2014 , ' BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability ' Cancer Research , vol 74 , no. 10 , pp. 2773-2784 . DOI: 10.1158/0008-5472.CAN-13-2611 |
Tipo |
article |