Abstract 3227: Lung-targeted expression of B-RAF V600E in alveolar type II cells causes emphysema and delayed adenoma in mice

Abstract

Abstract Classically oncogenes are found associated with neoplastic diseases. More recently a connection with developmental syndromes has been reported. Here we describe a link between the most prevalent mutant form of B-RAF oncogene (B-RAF V600E) with Chronic Obstructive Pulmonary Disease (COPD) that often precede lung cancer in men. By use of targeted expression of this mutant B-RAF in type II pneumocytes of mice we have developed an animal model for these devastating diseases that are epidemic worldwide. Constitutive expression of B-RAF V600E led to emphysema as early as late embryonic development that is persistent throughout adult life when it is often accompanied by chronic inflammation. Infiltrating immune cells include localized macrophages, mast cells, and leukocytes as in the case of human COPD. Inflammatory cell infiltration does not precede emphysema formation but is a prelude to tumor development. Consistently, ablation of RAG1 alleles did not eliminate emphysema or late tumor development. The oncogene involved in tumor formation is also B-RAF V600E because the most frequent mutations of spontaneous lung adenomas in mice were absent. These data support a model where the regenerative process triggered by continuous emphysema formation is the driving force that converts B-RAF V600E from a latent to an active oncogene in this target cell type. Our data suggest that B-RAF V600E is not a complete oncogene in type II cells and requires promoting conditions that can be provided by emphysema. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3227.