Lung premalignancy induced by mutant B-Raf, what is thy fate? To senesce or not to senesce, that is the question.

For more than 25 years, the Ras proteins have been widely accepted as central players in the malignant transformation of a variety of different tumor types. The ability of mutationally activated Ras to provide a powerful oncogenic stimulus lies in its capacity to signal through a multitude of downstream effector pathways that regulate a diverse set of cellular processes (for a recent review, see Downward 2006). It is only in the past several years that activating mutations in these Ras effector pathways have also been identified in human cancers. For example, mutations in PIK3CA are common in colon, gastric, and brain cancers (Samuels et al. 2004), while BRAF mutations occur at high frequency in melanomas, colon cancers, and ovarian cancers (Davies et al. 2002). In this issue of Genes & Development, Dankort et al. (2007) provide the first formal demonstration that mutationally activated B-Raf can act as the initiating event for lung tumorigenesis, further establishing B-Raf as a bona fide oncoprotein. But unlike the story with conventional oncogenes, like Ras, the B-Raf story has an interesting twist. Activating mutations in B-Raf are found in 3% of nonsmall-cell lung cancers (NSCLC) (Brose et al. 2002; Davies et al. 2002; Naoki et al. 2002). Dankort et al. (2007) have used gene targeting to create the first mouse model of B-Raf-induced lung tumorigenesis. In the absence of Cre recombinase, the engineered Braf allele (Braf, for Cre-activated) expresses a chimeric mRNA composed of exons 1–14 of the mouse gene and exons 15–18 of the wild-type BRAF gene from humans (Dankort et al. 2007). After Cre-mediated recombination, the human exons are removed and the mouse Braf is expressed in its entirety, including the V600E-activating mutation in exon 15 (Dankort et al. 2007). As with other mouse models of lung cancer, tumors were initiated in this new model by infecting the lung epithelium with Adenovirus carrying the gene for Cre recombinase (AdCre), which allows one to titrate the levels of Cre activity and also to temporally regulate Cre expression (Jackson et al. 2001). Importantly, the mutant form of B-Raf (B-Raf) is expressed from its endogenous locus in this model, mimicking what occurs in human cancers. Within 2–4 wk after infection with AdCre, lungs of B-Raf mice exhibited hyperplastic epithelium that progressed to papillary adenomas within 6–8 wk (Dankort et al. 2007). A striking feature of the B-Raf-mutant lung tumors from these animals was that they failed to progress to carcinoma, and instead, exhibited growth arrest and senescence-like features. This senescence-like phenotype could be overcome through concomitant mutation of p53 or p16/ p19, which allowed the tumors to progress to fullblown adenocarcinoma. Interestingly, B-Raf-induced senescence has also been observed in vivo in benign nevi, the precursor lesion to melanoma, although the role that p53 and p16 play in this process is not completely clear (Michaloglou et al. 2005). Several mouse models of NSCLC have been generated recently. Those relying on mutationally activated K-Ras as the initiating event most closely resemble the B-Raf model of Dankort et al. (2007). In two independent models, expression of the mutant form of K-Ras (K-Ras or K-Ras) from its endogenous promoter leads to the development of lung tumors that progress to full-blown adenocarcinoma (Jackson et al. 2001; Guerra et al. 2003), a stark contrast from the phenotype of expressing mutant B-Raf in the lung. Nevertheless, in their earliest stages of development, tumors initiated by K-Ras or B-Raf are similar in their histology and in their expression of markers for alveolar type 2 (AT2) cells. Thus, the early stages of tumorigenesis induced by B-Raf appear to phenocopy the early stages of K-Ras-induced tumorigenesis in the lung. Indeed, sequencing analysis of human tumors indicates that Ras and B-Raf mutations are mutually exclusive, suggesting that signaling through B-Raf is key to the oncogenic properties Corresponding author. E-MAIL [email protected]; FAX (713) 792-1220. Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1532107.