Abstract 4010: Significant roles of p120 catenin and MUC1 in promoting invasive behavior of pancreatic cancer cells

Abstract

Abstract Pancreatic cancer is highly lethal in part because the tumors have metastasized at the time of diagnosis. We are investigating the hypothesis that interactions between the cell surface mucin MUC1 and p120 catenin (p120ctn) modulate cell adhesion, invasion and metastatic properties of pancreatic cancer cells. MUC1 is overexpressed in pancreatic cancer and is known to modulate the invasive and metastatic properties of tumor cells by influencing cell surface adhesion properties directly and by signaling through the MUC1 cytoplasmic tail that reprogram transcription of invasion and metastasis associated genes. Downregulation or mislocalization of p120ctn is correlated with high grade and poor survival in human pancreatic cancer. E-cadherin, which is normally stabilized by p120 catenin in the cell membrane, is frequently lost or downregulated in various human cancers, resulting in the emergence of malignant characteristics, such as loss of epithelial morphology, and gain of invasiveness and metastatic potential. We hypothesized that MUC1 competed with binding of E-cadherin to p120ctn, which enhanced E-cadherin internalization, thus promoting epithelial to mesenchymal transition (EMT). We report here that several p120 catenin isoforms are expressed in human pancreatic cancer and that MUC1 cytoplasmic tail interacts with armadillo repeats of p120ctn. Overexpression of MUC1 resulted in alterations in expression of different p120ctn isoforms, increased nuclear localization of p120ctn, and a decrease in p120ctn association with E-cadherin, as detected by western blotting, co-immunoprecipitations, and confocal microscopy analysis of Capan1 and MIAPACA-2 pancreatic cancer cell lines. Our data support the hypothesis that MUC1 overexpression decreases the association of p120 catenin with E-cadherin, which increases E-cadherin turn over. We also detected colocalization of MUC1 and p120ctn in the nucleus, raising the possibility that this association constitutes a novel signaling pathway mediated by MUC1 and p120ctn that contribute to the reprograming of gene expression during EMT, invasion and metastasis. This research provides novel insight that enable opportunities to develop an effective therapy to prevent pancreatic tumor invasion and metastasis. Supported by grant R01CA57362 from the NCI. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4010. doi:10.1158/1538-7445.AM2011-4010