| RRC ID |
11933
|
| Author |
Shimizu M, Cohen B, Goldvasser P, Berman H, Virtanen C, Reedijk M.
|
| Title |
Plasminogen activator uPA is a direct transcriptional target of the JAG1-Notch receptor signaling pathway in breast cancer.
|
| Journal |
Cancer Res
|
| 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.
|
| Volume |
71(1)
|
| Pages |
277-86
|
| Published |
2011-1-1
|
| DOI |
10.1158/0008-5472.CAN-10-2523
|
| PII |
71/1/277
|
| PMID |
21199807
|
| MeSH |
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Calcium-Binding Proteins / metabolism*
Cell Line, Tumor
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
Female
Gene Expression Profiling
Humans
Immunohistochemistry
Intercellular Signaling Peptides and Proteins / metabolism*
Jagged-1 Protein
Membrane Proteins / metabolism*
Neoplasm Invasiveness
Neoplasm Metastasis
Receptors, Notch / metabolism*
Serrate-Jagged Proteins
Signal Transduction*
Transcription, Genetic*
Urokinase-Type Plasminogen Activator / physiology*
|
| IF |
9.727
|
| Times Cited |
38
|
|
WOS Category
|
ONCOLOGY
|
| Resource |
| DNA material |
pKM2L-phUPA p1966-9F (RDB05547) |
