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MUC1 drives c-Met-dependent migration and scattering.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2012 Dec; Vol. 10 (12), pp. 1544-54. Date of Electronic Publication: 2012 Nov 27. - Publication Year :
- 2012
-
Abstract
- The transmembrane mucin MUC1 is overexpressed in most ductal carcinomas, and its overexpression is frequently associated with metastatic progression. MUC1 can drive tumor initiation and progression via interactions with many oncogenic partners, including β-catenin, the EGF receptor (EGFR) and Src. The decoy peptide protein transduction domain MUC1 inhibitory peptide (PMIP) has been shown to inhibit the tumor promoting activities of MUC1 in breast and lung cancer, including cell growth and invasion, and its usage suppresses metastatic progression in mouse models of breast cancer. To further characterize the reduced metastasis observed upon PMIP treatment, we conducted motility assays and observed that PMIP inhibits cell motility of breast cancer cells. To determine the mechanism by which PMIP inhibits motility, we evaluated changes in global gene transcription upon PMIP treatment, and identified a number of genes with altered expression in response to PMIP. Among these genes is the metastatic mediator, c-Met, a transmembrane tyrosine kinase that can promote cell scattering, migration, and invasion. To further investigate the role of c-Met in MUC1-dependent metastatic events, we evaluated the effects of MUC1 expression and EGFR activation on breast cancer cell scattering, branching, and migration. We found that MUC1 strongly promoted all of these events and this effect was further amplified by EGF treatment. Importantly, the effect of MUC1 and EGF on these phenotypes was dependent upon c-Met activity. Overall, these results indicate that PMIP can block the expression of a key metastatic mediator, further advancing its potential use as a clinical therapeutic.
- Subjects :
- Breast Neoplasms genetics
Breast Neoplasms metabolism
Cell Line, Tumor
Cell Movement drug effects
Disease Progression
Down-Regulation drug effects
Epidermal Growth Factor pharmacology
ErbB Receptors genetics
ErbB Receptors metabolism
Female
Humans
Neoplasm Metastasis genetics
Neoplasm Metastasis pathology
Transcription, Genetic drug effects
Breast Neoplasms pathology
Cell Movement genetics
Mucin-1 genetics
Mucin-1 metabolism
Peptides pharmacology
Proto-Oncogene Proteins c-met genetics
Proto-Oncogene Proteins c-met metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 10
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 23193156
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-12-0296