Mutation of TGFβ-RII eliminates NSAID cancer chemoprevention

Juana Martín-López; Pierluigi Gasparini; Kevin Coombes; Carlo M. Croce; Gregory P. Boivin; Richard Fishel

doi:10.18632/oncotarget.23792

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Priority Research Papers:

Mutation of TGFβ-RII eliminates NSAID cancer chemoprevention

Juana Martín-López, Pierluigi Gasparini, Kevin Coombes, Carlo M. Croce, Gregory P. Boivin and Richard Fishel _

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Oncotarget. 2018; 9:12554-12561. https://doi.org/10.18632/oncotarget.23792

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Abstract

Juana Martín-López1, Pierluigi Gasparini1, Kevin Coombes2, Carlo M. Croce1, Gregory P. Boivin3 and Richard Fishel1,4

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+/-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 TGFβ receptor type-II (Tgfβ-RII) mutation in the VpC-Msh2 mouse (villin-Cre+/-Msh2flox/floxTgfβ−RIIflox/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.

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Priority Research Papers:

Mutation of TGFβ-RII eliminates NSAID cancer chemoprevention

Abstract