-Activated Cells Can Develop into Lung Tumors When -Mediated Tumor Suppressor Pathways Are Abrogated.

is frequently mutated in human lung adenocarcinomas (ADCs), and the p53 pathway plays a central role in cellular defense against oncogenic mutation. However, in mouse lung cancer models, oncogenic mutation alone can induce ADCs without mutation, and loss of p53 does not have a significant impact on early -induced lung tumorigenesis. These results raise the question of how -activated cells evade oncogene surveillance mechanisms and develop into lung ADCs. RUNX3 plays a key role at the restriction (R)-point, which governs multiple tumor suppressor pathways including the p14-p53 pathway. In this study, we found that activation in a very limited number of cells, alone or in combination with p53 inactivation, failed to induce any pathologic lesions for up to 1 year. By contrast, when Runx3 was inactivated and was activated by the same targeting method, lung ADCs and other tumors were rapidly induced. In a urethane-induced mouse lung tumor model that recapitulates the features of -driven human lung tumors, was inactivated in both adenomas (ADs) and ADCs, whereas was activated only in ADCs. Together, these results demonstrate that the R-point-associated oncogene surveillance mechanism is abrogated by Runx3 inactivation in AD cells and these cells cannot defend against activation, resulting in the transition from AD to ADC. Therefore, -activated lung epithelial cells do not evade oncogene surveillance mechanisms; instead, they are selected if they occur in AD cells in which has been inactivated.