Mutation of TGFβ-RII eliminates NSAID cancer chemoprevention

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

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12554-12561
Number of pages8
JournalOncotarget
Volume9
Issue number16
DOIs
StatePublished - 2018
Externally publishedYes

Keywords

  • COX-independent
  • Cardioprotection
  • Colon cancer
  • Mismatch repair
  • Naproxen

ASJC Scopus subject areas

  • Oncology

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