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MUC1-C Represses the Crumbs Complex Polarity Factor CRB3 and Downregulates the Hippo Pathway
- Source :
- Molecular Cancer Research. 14:1266-1276
- Publication Year :
- 2016
- Publisher :
- American Association for Cancer Research (AACR), 2016.
-
Abstract
- Apical–basal polarity and epithelial integrity are maintained in part by the Crumbs (CRB) complex. The C--terminal subunit of MUC1 (MUC1-C) is a transmembrane protein that is expressed at the apical border of normal epithelial cells and aberrantly at high levels over the entire surface of their transformed counterparts. However, it is not known whether MUC1-C contributes to this loss of polarity that is characteristic of carcinoma cells. Here it is demonstrated that MUC1-C downregulates expression of the Crumbs complex CRB3 protein in triple-negative breast cancer (TNBC) cells. MUC1-C associates with ZEB1 on the CRB3 promoter and represses CRB3 transcription. Notably, CRB3 activates the core kinase cassette of the Hippo pathway, which includes LATS1 and LATS2. In this context, targeting MUC1-C was associated with increased phosphorylation of LATS1, consistent with activation of the Hippo pathway, which is critical for regulating cell contact, tissue repair, proliferation, and apoptosis. Also shown is that MUC1-C--mediated suppression of CRB3 and the Hippo pathway is associated with dephosphorylation and activation of the oncogenic YAP protein. In turn, MUC1-C interacts with YAP, promotes formation of YAP/β-catenin complexes, and induces the WNT target gene MYC. These data support a previously unrecognized pathway in which targeting MUC1-C in TNBC cells (i) induces CRB3 expression, (ii) activates the CRB3-driven Hippo pathway, (iii) inactivates YAP, and thereby (iv) suppresses YAP/β-catenin–mediated induction of MYC expression. Implications: These findings demonstrate a previously unrecognized role for the MUC1-C oncoprotein in the regulation of polarity and the Hippo pathway in breast cancer. Mol Cancer Res; 14(12); 1266–76. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Down-Regulation
Apoptosis
Triple Negative Breast Neoplasms
Protein Serine-Threonine Kinases
Biology
Article
03 medical and health sciences
Cell Line, Tumor
Cell polarity
Humans
Hippo Signaling Pathway
Phosphorylation
Promoter Regions, Genetic
skin and connective tissue diseases
neoplasms
Molecular Biology
Transcription factor
Adaptor Proteins, Signal Transducing
Regulation of gene expression
Hippo signaling pathway
Membrane Glycoproteins
Kinase
Mucin-1
Wnt signaling pathway
Cell Polarity
Zinc Finger E-box-Binding Homeobox 1
Signal transducing adaptor protein
YAP-Signaling Proteins
Phosphoproteins
digestive system diseases
Cell biology
Gene Expression Regulation, Neoplastic
030104 developmental biology
Oncology
MCF-7 Cells
Cancer research
Female
Signal transduction
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 15573125 and 15417786
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Research
- Accession number :
- edsair.doi.dedup.....ae5a8354ff21c1a9adce9a58da5f5989