期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：41
DOI：10.1073/pnas.2108421118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
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 (∼90 to 120 d) than did wild-type (WT) mice, which remained largely tumor free. Their esophageal tissue, but not that of WT control mice, revealed evidence of overt RS as reflected by intracellular CHK1 phosphorylation and 53BP1 staining. These
Brca1 mutant tumors also revealed higher genome mutation rates than those of control animals; the mutational signature SBS4, which is associated with tobacco-induced tumorigenesis; and a loss of
Brca1 heterozygosity (LOH). This uniquely accelerated
Brca1 tumor model is also relevant to human esophageal squamous cell carcinoma, an often lethal tumor.
关键词：enBRCA1;replication stress;haploinsufficiency;mouse model
