Supplementary Figures 1 - 6 from 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

doi:10.1158/0008-5472.22398495.v1

Supplementary Figures 1 - 6 from BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

journal contribution

posted on 2023-03-30, 22:01 authored by Kienan I. Savage, Kyle B. Matchett, Eliana M. Barros, Kevin M. Cooper, Gareth W. Irwin, Julia J. Gorski, Katy S. Orr, Jekaterina Vohhodina, Joy N. Kavanagh, Angelina F. Madden, Alexander Powell, Lorenzo Manti, Simon S. McDade, Ben Ho Park, Kevin M. Prise, Stuart A. McIntosh, Manuel Salto-Tellez, Derek J. Richard, Christopher T. Elliott, D. Paul Harkin

PDF file - 2823K, Supplementary Figure 1. Estrogen metabolites cause DNA double strand breaks in S- phase cells. Supplementary Figure 2. BRCA1 supresses estrogen metabolite mediated DSBs and is required for their repair. Supplementary Figure 3. Estrogen and its metabolites induce DNA DSBs in a dose and time dependent manner. Supplementary Figure 4. BRCA1 suppresses estrogen metabolites induced DNA damage in BRCA1 mutant breast cancer cells. Supplementary Figure 5. BRCA1 and BRCA2 are required for repair of estrogen metabolite induced DSBs in MCF10A and MCF7 breast cells. Supplementary Figure 6. BRCA1, but not BRCA2, suppresses estrogen metabolite mediated DNA damage by repressing CYP1A1 expression in breast cells.

History

ARTICLE 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. Cancer Res; 74(10); 2773–84. ©2014 AACR.