Abstract 1587: Targeted deletion of Fra-1 blocks oncogenic K-ras induced lung tumor development and progression in mice

Abstract Background: Fra-1 (Fosl1) is a dimeric partner of AP-1 transcription factor and regulates gene expression in a context-dependent (cell-type and stimulus-specific) manner through the TPA response element (AP-1 site). We have previously shown that Fra-1 is strongly activated in lung epithelial cells by cigarette smoke, a major determinant of lung cancer, as well as tumor promoting mitogenic and pro-inflammatory stimuli. Ectopic expression of Fra-1 promotes human lung cancer cell progression in vitro, and tumor development in nude mice. We hypothesized that Fra-1, an effector of ERK signaling, is required for oncogenic K-ras promoted lung tumor development in vivo. Methods: To test our hypothesis and to better understand the role of Fra-1 in lung tumor development and progression in vivo, we have generated transgenic mice bearing floxed allele Fra-1 (Fra-1FF) and LSL K-rasG12D by cross-breeding Fra1F/F and LSL K-rasG12D mice (NCI), which carry a latent point-mutant allele of K-ras (K-rasG12D). Fra1wt/wt +LSL-K-rasG12D mice (abbreviated as Kras+/−) and Fra1F/F+ LSL-K-rasG12D mice (Fra1FF- K-rasG12D) were instilled intratracheally with adenovirus Cre (2.5 ×107 pfu) and then were allowed to recover for an additional 13 weeks. Mice were sacrificed, lungs were fixed, and lung tumor induction was analyzed by histopathology. Results: As anticipated, activation of K-ras oncogene by Ade-Cre instillation induced lung tumor development in Kras+/− mice bearing Fra-1 wild type alleles. Hyperplastic lesions with papillary structures and adenomas were clearly visible in these mice. Strikingly, the lung tumor formation in Fra-1 floxed mice bearing LSL-K-rasG12D allele (Fra1F/F+ LSL-K-rasG12D mice) infected with Adeno-cre virus was markedly reduced. In all animals, with exception of few hyperplastic lesions, no adenomas were detected in mice lacking Fra-1. Conclusions: The present data suggest that Fra-1 is critical for oncogenic K-ras promoted lung tumor development in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1587.