期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2108421118
关键词
BRCA1; replication stress; haploinsufficiency; mouse model
资金
- NIH
- Gray Foundation
- Breast Cancer Research Foun-dation
- Susan G. Komen Foundation
- BRCA Foundation
- Murray Winsten Foun-dation
- University of Massachusetts Startup Funds
- Dana-Farber/Harvard Cancer Center (DF/HCC) Breast SPORE CEP
- Breast Cancer Research Foundation [BCRF-20-159]
- Kraeftens Bekaempelse [R281-A16566]
- CDMRP Prostate Cancer Re-search Program [W81XWH-18-2-00560]
- Det Frie Forskningsrad Sundhed og Sygdom [7016-00345B]
- Basser Foundation
- Dana-Farber/Harvard Cancer Center Kidney Can-cer SPORE Grant [P50-CA101942-12]
BRCA1 heterozygous cells with unresolved replication stress have been shown to drive esophageal tumorigenesis, using 4NQO as an RS-inducing agent, resulting in higher tumor formation rates and genome mutation rates in Brca1 heterozygous mice compared to wild-type mice.
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 (similar to 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据