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

Brca1 deficiency exacerbates estrogen-induced dna damage and genomic instability / Savage, Ki; Matchett, Kb; Barros, Em; Cooper, Km; Irwin, Gw; Gorski, Jj; Orr, Ks; Vohhodina, J; Kavanagh, Jn; Madden, Af; Powell, A; Manti, Lorenzo; Mcdade, Ss; Park, Bh; Prise, Km; Mcintosh, Sa; Salto Tellez, M; Richard, Dj; Elliott, Ct; Harkin, Dp. - In: CANCER RESEARCH. - ISSN 0008-5472. - 74:10(2014), pp. 2773-2784. [10.1158/0008-5472.CAN-13-2611]

Brca1 deficiency exacerbates estrogen-induced dna damage and genomic instability

MANTI, LORENZO;
2014

Abstract

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
Brca1 deficiency exacerbates estrogen-induced dna damage and genomic instability / Savage, Ki; Matchett, Kb; Barros, Em; Cooper, Km; Irwin, Gw; Gorski, Jj; Orr, Ks; Vohhodina, J; Kavanagh, Jn; Madden, Af; Powell, A; Manti, Lorenzo; Mcdade, Ss; Park, Bh; Prise, Km; Mcintosh, Sa; Salto Tellez, M; Richard, Dj; Elliott, Ct; Harkin, Dp. - In: CANCER RESEARCH. - ISSN 0008-5472. - 74:10(2014), pp. 2773-2784. [10.1158/0008-5472.CAN-13-2611]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/597572
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