title: Diminished WNT -> β-catenin -> c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors.
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 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.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center.
authors.forename: Joseph
authors.initials: J
authors.lastname: Juan
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Muraguchi
authors.forename: Gioia
authors.initials: G
authors.lastname: Iezza
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D008175:Lung Neoplasms / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D051153:Wnt Proteins; D051176:beta Catenin; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; c-MYC; non-small-cell lung cancer; β-catenin