Ye He, Joshua Rivera, Miklos Diossy, Haohui Duan, Christian Bowman-Colin, Rachel Reed, Rebecca Jennings, Jesse Novak, Stevenson V Tran, Elizabeth F Cohen, David Szuts, Anita Giobbie-Hurder, Roderick T Bronson, Adam J Bass, Sabina Signoretti, Zoltan Szallasi, David M Livingston, Shailja Pathania
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...
October 12, 2021: Proceedings of the National Academy of Sciences of the United States of America