Diminished WNT → β-catenin → c-MYC signaling is a barrier for malignant progression of BRAF V600E -induced lung tumors

• Published in: Genes & development 2014-03, Vol.28 (6), p.561-575
• Main Authors: Juan, Joseph, Muraguchi, Teruyuki, Iezza, Gioia, Sears, Rosalie C., McMahon, Martin
• Format: Article
• Language: English
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.233627.113

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 BRAF V600E 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 BRAF V600E -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 BRAF V600E -initiated lung tumorigenesis. Conversely, sustained activity of β-catenin or c-MYC significantly enhanced BRAF V600E -induced lung tumorigenesis and rescued the anti-tumor effects of Porcupine blockade. These data indicate that early stage BRAF V600E -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 BRAF V600E -initiated lung tumors. Moreover, these data further suggest that the trigger for OIS in initiated BRAF V600E -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.