Mutation of TGF?-RII eliminates NSAID cancer chemoprevention.

ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) exhibit anti-neoplastic (chemoprevention) activity for sporadic cancers and the hereditary cancer predisposition Lynch syndrome (LS/HNPCC). However, the mechanism of NSAID tumor suppression has remained enigmatic. Defects in the core mismatch repair (MMR) genes MSH2 and MLH1 are the principal drivers of LS/HNPCC. Previous work has demonstrated that the villin-Cre+/-Msh2flox/flox (VpC-Msh2) mouse is a reliable model for LS/HNPCC intestinal tumorigenesis, which is significantly suppressed by treatment with the NSAID aspirin (ASA) similar to human chemoprevention. Here we show that including a TGF? receptor type-II (Tgf?-RII) mutation in the VpC-Msh2 mouse (villin-Cre+/-Msh2flox/floxTgf?-RIIflox/flox ) completely eliminates NSAID tumor suppression. These results provide strong genetic evidence that TGF? signaling and/or effectors participate in NSAID-dependent anti-neoplastic processes and provide fresh avenues for understanding NSAID chemoprevention and resistance.

SUBMITTER: Martin-Lopez J 

PROVIDER: S-EPMC5849154 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature