TP53 Silencing Bypasses Growth Arrest of BRAFV600E-Induced Lung Tumor Cells in a Two-Switch Model of Lung Tumorigenesis.

Abstract

Lung carcinogenesis is a multistep process in which normal lung epithelial cells are converted to cancer cells through the sequential acquisition of multiple genetic or epigenetic events. Despite the utility of current genetically engineered mouse (GEM) models of lung cancer, most do not allow temporal dissociation of the cardinal events involved in lung tumor initiation and cancer progression. Here we describe a novel two-switch GEM model for BRAF(V600E)-induced lung carcinogenesis allowing temporal dissociation of these processes. In mice carrying a Flp recombinase-activated allele of Braf (Braf(FA)) in conjunction with Cre-regulated alleles of Trp53, Cdkn2a, or c-MYC, we demonstrate that secondary genetic events can promote bypass of the senescence-like proliferative arrest displayed by BRAF(V600E)-induced lung adenomas, leading to malignant progression. Moreover, restoring or activating TP53 in cultured BRAF(V600E)/TP53(Null) or BRAF(V600E)/INK4A-ARF(Null) lung cancer cells triggered a G1 cell-cycle arrest regardless of p19(ARF) status. Perhaps surprisingly, neither senescence nor apoptosis was observed upon TP53 restoration. Our results establish a central function for the TP53 pathway in restricting lung cancer development, highlighting the mechanisms that limit malignant progression of BRAF(V600E)-initiated tumors.