Open AccessBRCA1/Trp53 heterozygosity and replication stress drive esophageal cancer development in a mouse model
Author(s) -
Ye He,
Joshua Rivera,
Miklós Dióssy,
Haohui Duan,
Christian Bowman-Colin,
Rachel Reed,
Rebecca B. Jennings,
Jesse Novak,
Stevenson Tran,
Elizabeth F. Cohen,
Dávid Szüts,
Anita GiobbieHurder,
Roderick T. Bronson,
Adam J. Bass,
Sabina Signoretti,
Zoltán Szállási,
David M. Livingston,
Shailja Pathania
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2108421118
Subject(s) - loss of heterozygosity , carcinogenesis , biology , cancer research , esophageal cancer , esophagus , 4 nitroquinoline 1 oxide , cancer , mutation , microbiology and biotechnology , genetics , allele , gene , anatomy
Significance Although germline heterozygousBRCA1 mutations predispose human carriers to cancer, heterozygous mouseBRCA1 mutations do not. We find that exposure to a source of upper gastrointestinal replication stress (RS) elicited a marked cancer incidence inBrca1 +/− ;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 esophagealBrca1 heterozygosity (LOH), and accelerated esophageal tumorigenesis. These data underscore the necessity of combining otherwise nontumorigenicBRCA1 heterozygosity with simultaneous induction of RS for the generation of not onlyBRCA1 mutant esophageal cancer, but also a dramatically accelerated form thereof. These results strongly imply that RS is both a major contributor toBRCA1 cancer development and a marked accelerant thereof.