Abstract 4433: RB mediates TGF-β effects on growth inhibition and invasion in pancreatic cancer cells

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that arises from precursor lesions, termed pancreatic intraepithelial neoplasia (PanIN). PDAC's aggressiveness derives from its advanced stage when patients present clinically, the high frequency of driver mutations (KRAS, INK4A, TP53 and SMAD4) and the heterogeneous distribution of low frequency driver mutations. To study the potential role of RB in PDAC pathobiology, we generated a novel mouse model with pancreatic RB deletion and oncogenic Kras expression (Rb/K mice). These mice rapidly developed highly proliferative PanIN that progress to PDAC with high frequency, underscoring RB's tumor suppressive role in the pancreas. RB deletion alone, however, did not alter pancreatic histology. Previously, we have demonstrated that Smad7-induced loss of TGF-β-mediated growth inhibition is due to functional inactivation of RB. To further examine RB's role in TGF-β action, we established pancreatic cancer cell lines from the Rb/K model. These cells were resistant to TGF-β1-mediated growth inhibition, whereas growth of murine cell lines that retained RB was markedly inhibited. RB loss also abolished TGF-β-induced cell invasion, but did not alter Smad-dependent TGF-β1 signaling since TGF-β1 induced Smad2 phosphorylation, Smad3/4 nuclear translocation, and transactivation of TGF-β1-dependent reporters. By contrast, RB loss did not affect TGF-β1-induced epithelial-to-mesenchymal transition. Array analysis revealed marked alterations in the gene expression profile of Rb/K cells. These data suggest that RB loss contributes to the dysregulation of TGF-β actions in PDAC and suggest that delineation of these perturbations may yield novel therapeutic approaches in this malignancy. 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 4433. doi:1538-7445.AM2012-4433