| First Author | Juan J | Year | 2014 |
| Journal | Genes Dev | Volume | 28 |
| Issue | 6 | Pages | 561-75 |
| PubMed ID | 24589553 | Mgi Jnum | J:209631 |
| Mgi Id | MGI:5568200 | Doi | 10.1101/gad.233627.113 |
| Citation | Juan J, et al. (2014) Diminished WNT -> beta-catenin -> c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors. Genes Dev 28(6):561-75 |
| abstractText | 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 beta-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 beta-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 beta-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 --> beta-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 --> beta-catenin --> c-MYC signaling. These data have implications for understanding how genetic abnormalities cooperate to initiate and promote lung carcinogenesis. |
