BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability

Savage, Kienan I., Matchett, Kyle B., Barros, Eliana M., Cooper, Kevin M., Irwin, Gareth W., Gorski, Julia J., Orr, Katy S., Vohhodina, Jekaterina, Kavanagh, Joy N., Madden, Angelina F., Powell, Alexander, Manti, Lorenzo, McDade, Simon S., Park, Ben Ho, Prise, Kevin M., McIntosh, Stuart A., Salto-Tellez, Manuel, Richard, Derek J., Elliott, Christopher T., & Harkin, D. Paul (2014) BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability. Cancer Research, 74(10), pp. 2773-2784.

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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 receptor-α 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-metabolising enzymes, such as CYP1A1, in breast cells. Lastly, 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 tumours in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

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25 citations in Scopus
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20 citations in Web of Science®

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ID Code: 84734
Item Type: Journal Article
Refereed: Yes
Keywords: BRCA1, Estrogen, Estrogen Metabolism, DNA damage, Genomic Instability
DOI: 10.1158/0008-5472.CAN-13-2611
ISSN: 1538-7445
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2014 American Association for Cancer Research
Deposited On: 11 Jun 2015 23:07
Last Modified: 16 May 2016 08:11

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