Besmer, Dahlia M.

Abstract MUC1 is over expressed and aberrantly glycosolated in >60% of pancreatic ductal adenocarcinomas. Over expression of MUC1 in pancreatic cancer is known, however the functional role has yet to be fully elucidated due to a dearth of appropriate models. In the present study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1 null (KCKO) or express human MUC1 as a self antigen (KCM). We show that PDA mice lacking Muc1 have significantly slower tumor progression, with tumor weight reaching up to a third of the KCM tumor and half of KC tumor. One out of 10 KCKO mice developed secondary metastasis versus 6 out of 10 and 3 out of 10 KCM and KC respectively. Cell lines derived from KCKO tumors have significantly lower tumorigenic capacity compared to cells derived from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared to mice bearing the KCM tumors. In vitro, the KCKO cells have reduced proliferation and invasion compared to KCM cells and failed to respond to exogenous epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or matrix metalloproteinase-9 (MMP9) stimuli. Further, significantly fewer KCKO cells entered the G2M phase of the cell cycle compared to the KCM cells, consequently more KCKO cells were observed at the S-phase of the cell cycle. Proteomics and western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of MAPK, as well as a significant decrease in Nestin and Tubulin α-2 chain expression in KCKO cells. Treatment of the KCM cells with a MEK1/2 inhibitor, U0126, completely abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, strongly suggesting that MUC1 is necessary for MAPK activity and downstream oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse in order to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. 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 1070. doi:10.1158/1538-7445.AM2011-1070

Abstract MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G2–M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. Cancer Res; 71(13); 4432–42. ©2011 AACR.