title: Identification of FRA-1 as a novel player in pancreatic cancer in cooperation with a MUC1: ERK signaling axis.
abstract: The MUC1 glycoprotein is overexpressed and aberrantly glycosylated in >90% of pancreatic ductal adenocarcinoma cases and impacts tumor progression by initiating downstream signaling through phosphorylation of its cytoplasmic tail. Previous studies have demonstrated that MUC1 alters expression of known targets of activator protein 1 (AP-1); however, no studies have evaluated the precise impact of MUC1 signaling on the activity and formation of AP-1. Given the known role of these proteins in modulating migration, invasion, and tumor progression, we explored the effects of MUC1 on AP-1 dimer formation and function. We determined that MUC1 increased the protein levels of c-Jun, the major component of AP-1, and promoted dimerization of c-Jun with the Fos-protein FRA-1. We demonstrate that FRA-1 acts as a potent mediator of migration and invasion in a manner that is modulated by signals through MUC1, which acts as a dominant regulator of specific AP-1 and FRA-1 target genes. Our results provide the first in vivo evidence of a FRA-1 mediated expression profile that impacts pancreatic tumor growth properties. In summary, we show that MUC1 enhancement of ERK activation influences FRA-1 activity to modulate tumor migration, invasion and metastasis in a subset of pancreatic cancer cases.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Hanson
authors.affiliation: University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Brown
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Steele
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Grandgenett
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Grunkemeyer
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006801:Humans; D051379:Mice; D018396:Mucin-1 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D000099169:Fos-Related Antigen 1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D018396:Mucin-1; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D000099169:Fos-Related Antigen 1; C060192:MUC1 protein, human
keywords: ERK; FRA-1; MUC1; invasion; pancreatic cancer