LIM-domain only (LMO) 7 is a multifunctional protein that is predicted to regulate the actin cytoskeleton, assembly of adherens junctions in epithelial cells, and gene expression. LMO7 was highly expressed in the mouse lung and predominantly localized to the apical membrane domain of bronchiolar epithelial cells. Although mice lacking LMO7 were viable and fertile in specific pathogen-free conditions, they developed protruding epithelial lesions in the terminal and respiratory bronchioles and alveolar ducts at 14-15 weeks of age. Furthermore, they tended to develop spontaneous adenocarcinoma in the lung at over 90 weeks of age. The cumulative incidence ratios of lung cancer were 22% in LMO7(-/-) mice and 13% in LMO7(+/-) mice whereas no primary lung cancer was observed in wild-type mice. Ex vivo analyses of the cancer cells showed numerical chromosome abnormalities and tumorigenicity in nude mice. These results suggest that LMO7 can act as a tumor suppressor whose deficiency confers a genetic predisposition to naturally occurring lung cancer.