Abstract

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.

Details

Title
Brca2 deficiency drives gastrointestinal tumor formation and is selectively inhibited by mitomycin C
Author
Chen, Xiaomin 1 ; Peng Fangfei 1 ; Ji, Yan 2 ; Xiang Honggang 3 ; Wang, Xiang 1 ; Liu, Tingting 1 ; Wang, Heng 1 ; Han, Yumin 1 ; Wang, Changxu 1 ; Zhang, Yongfeng 1 ; Kong Xiangyin 1 ; Jing-Yu, Lang 1   VIAFID ORCID Logo 

 Chinese Academy of Sciences, CAS_Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309) 
 Chinese Academy of Sciences, Bioinformatics Core, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309) 
 Pudong New Area People’s Hospital affiliated to Shanghai University of Medicine & Health Science, Department of General Surgery, Shanghai, China (GRID:grid.507037.6) 
Publication year
2020
Publication date
Sep 2020
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2449452214
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.