<i>BRCA1/Trp53</i> heterozygosity and replication stress drive esophageal cancer development in a mouse model

Abstract

Significance Although germline heterozygous BRCA1 mutations predispose human carriers to cancer, heterozygous mouse BRCA1 mutations do not. We find that exposure to a source of upper gastrointestinal replication stress (RS) elicited a marked cancer incidence in Brca1 +/− ;Trp53 +/− heterozygous mice but not in wild-type mice ( Brca1 +/+ ;Trp53 +/− ). Oral delivery of 4 nitroquinoline-1-oxide induced esophageal epithelial RS, an increased esophageal mutation rate, loss of esophageal Brca1 heterozygosity (LOH), and accelerated esophageal tumorigenesis. These data underscore the necessity of combining otherwise nontumorigenic BRCA1 heterozygosity with simultaneous induction of RS for the generation of not only BRCA1 mutant esophageal cancer, but also a dramatically accelerated form thereof. These results strongly imply that RS is both a major contributor to BRCA1 cancer development and a marked accelerant thereof.