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

Menée à l'aide de modèles murins, cette étude met en évidence le rôle du stress réplicatif et du caractère hétérozygote des gènes BRCA1 et Trp53 dans le développement d'un cancer de l'oesophage

Résumé en anglais

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.BRCA1 germline mutations are associated with an increased risk of breast and ovarian cancer. Recent findings of others suggest that BRCA1 mutation carriers also bear an increased risk of esophageal and gastric cancer. Here, we employ a Brca1/Trp53 mouse model to show that unresolved replication stress (RS) in BRCA1 heterozygous cells drives esophageal tumorigenesis in a model of the human equivalent. This model employs 4-nitroquinoline-1-oxide (4NQO) as an RS-inducing agent. Upon drinking 4NQO-containing water, Brca1 heterozygous mice formed squamous cell carcinomas of the distal esophagus and forestomach at a much higher frequency and speed (