Abstract 2347: Translational control and lung cancer: eIF4F activation promotes tumorigenesis in vivo
Authors: McCauley Joel A. , Evenson Kristen , Truitt Morgan , Kratzke Robert , Polunovsky Vitaly , Ruggero Davide , BItterman Peter , D'Cunha Jonathan 
Published: August 2012

Abstract
Introduction: Lung cancer is the number one cancer killer in the United States accounting for nearly 30% of all cancer deaths. Survival rates continue to be abysmal with 5-year survival only 15% despite contemporary therapies, making it clear that novel therapeutic agents need to be discovered. The translation of mRNA into protein, a central control point in the gene expression pathway, has been increasingly implicated as a critical checkpoint in tumor genesis and progression. This checkpoint serves as a traffic signal at the intersection of cell pathways controlling cell division and survival. The cell machinery controlling the first step in protein synthesis, a hetero-trimer designated eIF4F, is stuck in the “on” position in many human cancers. When this happens cells evade restraints on proliferation and survival. The activation state of eIF4F is controlled at multiple levels with the primary mechanism being negative regulation by the 4E binding proteins (4E-BPs). 4E-BPs are inactivated when phosphorylated via mTOR in response to pro-growth signaling enabling eukaryotic initiation factor 4E (eIF4E), the rate-limiting component of the eIF4F heterotrimer, to activate translation. When de-phosphorylated, 4E-BPs bind eIF4E thereby inhibiting translation. In this study we examined the effects of eIF4F activation, via over-expression of eIF4E or knock-out of 4E-BPs, on lung tumorigenesis. Methods: Two transgenic mouse models of eIF4F activation were developed: 1) The αactin-eIF4E mouse model was crossed with the LSL-KrasG12D model resulting in the development of a 4E/KrasG12D double transgenic model. 2) The 4E-BP1, BP2 knockout mouse model was crossed with the LSL-KrasG12D model to produce a BPDKO/KrasG12D triple transgenic model. LSL-KrasG12D, 4E/KrasG12D, and BPDKO/KrasG12D mice were intranasally administered 2.5x104 infectious particles of replication deficient adenovirus expressing Cre recombinase (Ad-Cre). Lungs were resected at 30 days post transfection, formalin-fixed, and paraffin embedded. Lung sections underwent H&E staining as well as IHC for Ki-67. Slides were digitally scanned and analyzed with Aperio ImageScope Software. Results: At 30 days there is a clear shift towards increased tumorigenesis in 4E/KrasG12D and BPDKO/KrasG12D mice as determined by histology. Ki-67 staining indicates a significant increase in cellular proliferation in 4E/KrasG12D and BPDKO/KrasG12D mice. Conclusions: Activated eIF4F, achieved by eIF4E overexpression or 4E-BP1,2 knockout, promotes tumorigenesis in combination with oncogenic KrasG12D. These transgenic mouse models can be used to both deconstruct the translational checkpoint in lung cancer and as a treatment model for translational inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2347. doi:1538-7445.AM2012-2347