Transmembrane mucin MUC1 is highly expressed in pancreatic adenocarcinoma and contributes to tumor growth, invasion, and metastasis. Differential phosphorylation of the cytoplasmic tail of MUC1 (MUC1.CT) by growth factor receptor tyrosine kinases is associated with morphogenetic signal transduction, as it enables interactions with signal transducers and leads to nuclear accumulation of MUC1.CT. MUC1.CT contains no known DNA binding motif but localizes to promoters of genes implicated in tumorigenesis in complex with transcription factors, modulating their regulatory activity. Using microarray analysis, we identified genes differentially transcribed in S2013 pancreatic adenocarcinoma cells stably overexpressing MUC1. These data were correlated with transcriptional targets of MUC1.CT identified on a genome-wide scale in pancreatic adenocarcinoma cells using a combination of chromatin immunoprecipitation and promoter array methodologies (ChIP-on-chip). We further investigated the transcriptional regulation of one novel target, connective tissue growth factor (CTGF/CCN2), by MUC1.CT. CTGF is highly expressed in pancreatic cancer and is a known mediator of tumor growth, angiogenesis, and metastasis. Overexpression of MUC1 significantly increased CTGF expression in pancreatic tumor cells in response to EGF, PDGF-BB, or HGF stimulation. The MUC1.CT becomes phosphorylated by EGFR, PDGFR-beta, and c-Met and overexpression of MUC1 constructs harboring mutations within the target phosphorylation motifs for these receptor tyrosine kinases reduced CTGF expression. We determined that MUC1.CT directly regulated the CTGF gene transcription through co-occupancy with transcription factors at several regions within and surrounding the CTGF promoter. MUC1 overexpression promoted localization of mutant p53 (R273H) and beta-catenin to the CTGF promoter, while decreasing occupancy by a repressor of CTGF transcription, c-Jun. We propose that MUC1, when overexpressed in pancreatic adenocarcinoma, enables expression of CTGF in response to growth factor stimulations by promoting mutant p53 and beta-catenin transcriptional activity and alleviating CTGF transcriptional repression by c-Jun. Taken together, these results reveal a novel signaling pathway that selectively induces CTGF expression in MUC1-overexpressing pancreatic tumor cells.

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 5077.