Mutation of TGFβ-RII eliminates NSAID cancer chemoprevention

// Juana Martín-López 1 , Pierluigi Gasparini 1 , Kevin Coombes 2 , Carlo M. Croce 1 , Gregory P. Boivin 3 and Richard Fishel 1,4 1 Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA 2 Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, OH, USA 3 Department of Pathology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA 4 Department of Physics, The Ohio State University, Columbus, OH, USA Correspondence to: Richard Fishel, email: // Keywords : COX-independent; cardioprotection; mismatch repair; naproxen; colon cancer Received : September 21, 2017 Accepted : November 15, 2017 Published : December 31, 2017 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 +/- Msh2 flox/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 TGFβ receptor type-II ( Tgfβ-RII ) mutation in the VpC-Msh2 mouse ( villin - Cre +/- Msh2 flox/flox Tgfβ − RII flox/flox ) completely eliminates NSAID tumor suppression. These results provide strong genetic evidence that TGFβ signaling and/or effectors participate in NSAID-dependent anti-neoplastic processes and provide fresh avenues for understanding NSAID chemoprevention and resistance.