title: Plasminogen activator uPA is a direct transcriptional target of the JAG1-Notch receptor signaling pathway in breast cancer.
abstract: Aberrant activation of the Notch receptor signaling pathway and overexpression of the Notch ligand JAG1 are associated with poor outcome in breast cancer. The plasminogen activator system, which includes urokinase-type plasminogen activator (uPA), has been validated as a marker of recurrence, high metastasis risk and death in breast malignancy. By using microarray profiling of breast cancer cell lines that had undergone siRNA-mediated abrogation of Notch signaling we uncovered a link between activated Notch signaling and uPA expression. An association between elevated expression of the Notch ligand JAG1, uPA, and the basal-like breast cancer subtype was confirmed in breast cancer cell lines. The association between JAG1 and uPA expression persisted in a survey of primary carcinomas of the breast. We found that Notch knockdown reduced transcription of uPA and phenocopied uPA knockdown in breast cancer cells. Through mutational analysis we identified a CBF-1 binding site in the uPA promoter that is required for direct transcriptional regulation by Notch. These data suggest that JAG1-induced Notch activation results in breast cancer progression through upregulation of the plasminogen activator system, directly linking these 2 important pathways of poor prognosis.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Brenda
authors.initials: B
authors.lastname: Cohen
authors.forename: Pavel
authors.initials: P
authors.lastname: Goldvasser
authors.forename: Hal
authors.initials: H
authors.lastname: Berman
authors.forename: Carl
authors.initials: C
authors.lastname: Virtanen
authors.forename: Michael
authors.initials: M
authors.lastname: Reedijk
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014158:Transcription, Genetic; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D014568:Urokinase-Type Plasminogen Activator