Media type: E-Article Title: Plasminogen Activator uPA Is a Direct Transcriptional Target of the JAG1-Notch Receptor Signaling Pathway in Breast Cancer Contributor: Shimizu, Mamiko; Cohen, Brenda; Goldvasser, Pavel; Berman, Hal; Virtanen, Carl; Reedijk, Michael imprint: American Association for Cancer Research (AACR), 2011 Published in: Cancer Research Language: English DOI: 10.1158/0008-5472.can-10-2523 ISSN: 0008-5472; 1538-7445 Keywords: Cancer Research ; Oncology Origination: Footnote: Description: <jats:title>Abstract</jats:title> <jats:p>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. Cancer Res; 71(1); 277–86. ©2010 AACR.</jats:p> Access State: Open Access