Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis

Dahlia M. Besmer, Jennifer M. Curry, Lopamudra D. Roy, Teresa L. Tinder, Mahnaz Sahraei, Jorge Schettini, Sun Il Hwang, Yong Y. Lee, Sandra J. Gendler, Pinku Mukherjee

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79 Scopus citations

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 G 2-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.

Original languageEnglish (US)
Pages (from-to)4432-4442
Number of pages11
JournalCancer research
Volume71
Issue number13
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Besmer, D. M., Curry, J. M., Roy, L. D., Tinder, T. L., Sahraei, M., Schettini, J., Hwang, S. I., Lee, Y. Y., Gendler, S. J., & Mukherjee, P. (2011). Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis. Cancer research, 71(13), 4432-4442. https://doi.org/10.1158/0008-5472.CAN-10-4439