1. ¹Department of Pediatrics and Genetics, Stanford Medical School, Stanford, CA, USA
2. ²Department of Pathology, Cancer Research Institute, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA

Correspondence: Dr J Sage, Department of Pediatrics and Genetics, Stanford Medical School, 269 Campus Drive, CCSR1215a, Stanford, CA 94305-5149, USA. E-mail: julien.sage@stanford.edu

³These authors contributed equally to this work.

Received 12 June 2008; Revised 16 October 2008; Accepted 16 December 2008; Published online 19 January 2009.

Abstract

Mutations of the retinoblastoma tumor suppressor gene RB are frequently observed in human cancers, but rarely in non-small cell lung carcinomas (NSCLCs). Emerging evidence also suggests that the RB-related gene p130 is inactivated in a subset of human NSCLCs. To directly test the specific tumor suppressor roles of RB and p130 in NSCLC, we crossed Rb and p130 conditional mutant mice to mice carrying a conditional oncogenic K-Ras allele. In this model, controlled oncogenic K-Ras activation leads to the development of adenocarcinoma, a major subtype of NSCLC. We found that loss of p130 accelerated the death of mice, providing direct evidence in vivo that p130 is a tumor suppressor gene, albeit a weak one in this context. Loss of Rb increased the efficiency of lung cancer initiation and resulted in the development of high-grade adenocarcinomas and rapid death. Thus, despite the low frequency of RB mutations in human NSCLCs and reports that K-Ras activation and loss of RB function are rarely found in the same human tumors, loss of Rb clearly cooperates with activation of oncogenic K-Ras in lung adenocarcinoma development in mice.