Diminished WNT → β-catenin → c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors

Joseph Juan, Teruyuki Muraguchi, Gioia Iezza, Rosalie C. Sears, Martin McMahon

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Oncogene-induced senescence (OIS) is proposed as a cellular defense mechanism that restrains malignant progression of oncogene-expressing, initiated tumor cells. Consistent with this, expression of BRAFV600E in the mouse lung epithelium elicits benign tumors that fail to progress to cancer due to an apparent senescence-like proliferative arrest. Here we demonstrate that nuclear β-catenin → c-MYC signaling is essential for early stage proliferation of BRAFV600E-induced lung tumors and is inactivated in the subsequent senescence-like state. Furthermore, either β-catenin silencing or pharmacological blockade of Porcupine, an acyl-transferase essential for WNT ligand secretion and activity, significantly inhibited BRAFV600E-initiated lung tumorigenesis. Conversely, sustained activity of β-catenin or c-MYC significantly enhanced BRAFV600E-induced lung tumorigenesis and rescued the anti-tumor effects of Porcupine blockade. These data indicate that early stage BRAFV600E-induced lung tumors are WNT-dependent and suggest that inactivation of WNT → β-catenin → c-MYC signaling is a trigger for the senescence-like proliferative arrest that constrains the expansion and malignant progression of BRAFV600E-initiated lung tumors. Moreover, these data further suggest that the trigger for OIS in initiated BRAFV600E-expressing lung tumor cells is not simply a surfeit of signals from oncogenic BRAF but an insufficiency of WNT → β-catenin → c-MYC signaling. These data have implications for understanding how genetic abnormalities cooperate to initiate and promote lung carcinogenesis.

Original languageEnglish (US)
Pages (from-to)561-575
Number of pages15
JournalGenes and Development
Volume28
Issue number6
DOIs
StatePublished - Mar 15 2014

Keywords

  • BRAF
  • Non-small-cell lung cancer
  • c-MYC
  • β-catenin

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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