| First Author | Chen X | Year | 2020 |
| Journal | Cell Death Dis | Volume | 11 |
| Issue | 9 | Pages | 812 |
| PubMed ID | 32980867 | Mgi Jnum | J:305816 |
| Mgi Id | MGI:6705627 | Doi | 10.1038/s41419-020-03013-8 |
| Citation | Chen X, et al. (2020) Brca2 deficiency drives gastrointestinal tumor formation and is selectively inhibited by mitomycin C. Cell Death Dis 11(9):812 |
| abstractText | BRCA2 is crucial for repairing DNA double-strand breaks with high fidelity, and loss of BRCA2 increases the risks of developing breast and ovarian cancers. Herein, we show that BRCA2 is inactively mutated in 10% of gastric and 7% of colorectal adenocarcinomas, and that this inactivation is significantly correlated with microsatellite instability. Villin-driven Brca2 depletion promotes mouse gastrointestinal tumor formation when genome instability is increased. Whole-genome screening data showed that these BRCA2 monoallelic and biallelic mutant tumors were selectively inhibited by mitomycin C. Mechanistically, mitomycin C provoked double-strand breaks in cancer cells that often recruit wild-type BRCA2 for repair; the failure to repair double-strand breaks caused cell-cycle arrest at the S phase and p53-mediated cell apoptosis of BRCA2 monoallelic and biallelic mutant tumor cells. Our study unveils the role of BRCA2 loss in the development of gastrointestinal tumors and provides a potential therapeutic strategy to eliminate BRCA2 monoallelic and biallelic mutant tumors through mitomycin C. |
