Abstract 3149: 4E-BP1 loss of function in pancreatic carcinogenesis

Inactivation of the transcription factor Smad4/DPC4 gene is a frequent event that correlates with aggressiveness of pancreatic adenocarcinomas. We have previously shown that the stress-inducible translational inhibitor 4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation. Here, we show that 4E-BP1 expression parallels that of Smad4 through the graded stages of pancreatic cancer progression. 4E-BP1 amount transiently increases in human PanIN-1 and PanIN-2 lesions, but is dramatically diminished in PanIN-3 and invasive carcinomas. A similar pattern of 4E-BP1 expression is seen in PanINs from pancreas of mice that carry a pancreas-specific mutated Kras allele (Kras-Pdx1/cre mice). Furthermore, we show in vitro that 4E-BP1 expression is efficiently induced under hypoxia in Smad4+/+, but not in Smad4−/− pancreatic duct cells. We further reveal that, at the molecular level, Smad4 cooperates with HIF1-alpha to induce 4E-BP1 gene transcription in hypoxic cells. Thus, it appears that pancreatic duct cells which carry Smad4 loss are no longer capable of inducing 4E-BP1 under stress conditions. This may have important consequences in pancreatic carcinogenesis as 4E-BP1 is viewed as a stress-inducible factor whose function is to block cellular protein synthesis to concentrate resources on an appropriate stress response aimed at restraining carcinogenesis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 3149.