title: Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis.
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.
authors.affiliation: Department of Biology, University of North Carolina, Charlotte, North Carolina 28223, USA.
authors.forename: Dahlia M
authors.initials: DM
authors.lastname: Besmer
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Curry
authors.forename: Lopamudra D
authors.initials: LD
authors.lastname: Roy
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Tinder
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Sahraei
authors.forename: Jorge
authors.initials: J
authors.lastname: Schettini
authors.forename: Sun-Il
authors.initials: SI
authors.lastname: Hwang
authors.forename: Yong Y
authors.initials: YY
authors.lastname: Lee
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D004815:Epidermal Growth Factor; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D064231:Nestin; D009570:Nitriles / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014404:Tubulin / Q000096:biosynthesis
chemical_list: D002070:Butadienes; D007381:Intermediate Filament Proteins; D018396:Mucin-1; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D014404:Tubulin; C113580:U 0126; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9