title: BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability.
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-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.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Kienan I
authors.initials: KI
authors.lastname: Savage
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Matchett
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Eliana M
authors.initials: EM
authors.lastname: Barros
authors.affiliation: Institute for Global Food Security, Queen's University Belfast, 30 Malone Rd, Belfast BT9 5BN, UK.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Cooper
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Irwin
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Gorski
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Katy S
authors.initials: KS
authors.lastname: Orr
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Jekaterina
authors.initials: J
authors.lastname: Vohhodina
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Joy N
authors.initials: JN
authors.lastname: Kavanagh
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Angelina F
authors.initials: AF
authors.lastname: Madden
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.|Institute for Global Food Security, Queen's University Belfast, 30 Malone Rd, Belfast BT9 5BN, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Powell
authors.affiliation: Radiation Biophysics Laboratory, Department of Physics, University of Naples Federico II, Via Cinthia-80126 Naples, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Manti
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Simon S
authors.initials: SS
authors.lastname: McDade
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Prise
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: McIntosh
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, 4059, Brisbane, Australia.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Richard
authors.affiliation: Institute for Global Food Security, Queen's University Belfast, 30 Malone Rd, Belfast BT9 5BN, UK.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Elliott
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
authors.forename: D Paul
authors.initials: DP
authors.lastname: Harkin
mesh_terms: D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D001940:Breast / Q000187:drug effects* / Q000502:physiology*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D002393:Estrogens, Catechol / Q000494:pharmacology; D005260:Female; D042822:Genomic Instability; D006801:Humans; D061986:MCF-7 Cells
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004967:Estrogens; D002393:Estrogens, Catechol; D004958:Estradiol; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1