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Pten Inactivation Accelerates Oncogenic K-ras–Initiated Tumorigenesis in a Mouse Model of Lung Cancer

Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² Pathology, and ³ Pulmonary Medicine, University of Texas-M. D. Anderson Cancer Center; Departments of ⁴ Molecular and Cellular Biology and ⁵ Molecular and Human Genetics and ⁶ Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas; ⁷ Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁸ Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Jonathan M. Kurie, Unit 432, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-792-1220; E-mail: jkurie{at}mdanderson.org.

Key Words: Pten • K-ras • lung cancer • mouse models

Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non–small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis. [Cancer Res 2008;68(4):1119–27]