A COOPERATIVE MODEL FOR PANCREATIC CANCER

Abstract

Alterations in the TGFβ pathways have been found to be present in pancreatitis and more than 50% of pancreatic tumors. In transgenic animals, functional inactivation of TGFβ signaling targeted to acinar cells results in increased proliferation of pancreatic acinar cells and severely perturbed acinar differentiation. Unfortunately, with the exception of few proteins, the molecular machinery responsible for the long-term changes by which TGFβ induces neoplastic transformation in both, human and experimental models is not well understood. To better define the molecular events that participate in carcinogenesis by TGFβ inactivation, here, we have sought to characterize novel molecular alterations in the pancreas of mice overexpressing dominant negative TGFβ Receptor II, which results in inactivation of the TGFβ pathway, by using a combination of gene profiling and bioinformatics-based pathway reconstruction modeling. Subsequently, we chose to further characterize the expression and function on the most significantly upregulated gene, E6AP, which is an ubiquitin protein ligase displaying oncogenic properties by directly marking p53 for degradation by 26S proteasome. Further analysis and validation of these results by RT-PCR and immunohistochemical methods demonstrated increased expression of this molecule in the acinar cell compartment of TGFβ inactive mutants. Studies performed in pancreatic cells using inactivating mutants or constitutively active variants of several members of the TGFβ pathway reveal that the mechanisms involved in TGFβ regulation of E6AP are SMAD-independent. Thus, these results, using a controlled genetic animal model, suggest that the TGFβ and p53 tumor suppressor pathways are functionally interdependent and may crosstalk at the level of E6AP. Our findings distinctively represent excellent mechanistic information supporting the tumor suppressor role of TGFβ through E6AP from the p53 pathway.