Nolan, M. E., Aranda, V., Lee, S., Lakshmi, B., Basu, S., Allred, D. C., Muthuswamy, S. K. (October 2008) The polarity protein Par6 induces cell proliferation and is overexpressed in breast cancer. Cancer Res, 68 (20). pp. 8201-9.
Abstract
The polarity protein complex Par6/atypical protein kinase (aPKC)/Cdc42 regulates polarization processes during epithelial morphogenesis, astrocyte migration, and axon specification. We, as well as others, have shown that this complex is also required for disruption of apical-basal polarity during the oncogene ErbB2-induced transformation and transforming growth factor beta-induced epithelial-mesenchymal transition of mammary epithelial cells. Here, we report that expression of Par6 by itself in mammary epithelial cells induces epidermal growth factor-independent cell proliferation and development of hyperplastic three-dimensional acini without affecting apical-basal polarity. This is dependent on the ability of Par6 to interact with aPKC and Cdc42, but not Lgl and Par3, and its ability to promote sustained activation of MEK/ERK signaling. Down-regulation of Cdc42 or aPKC expression suppresses the ability of Par6 to induce proliferation, demonstrating that Par6 promotes cell proliferation by interacting with aPKC and Cdc42. We also show that Par6 is overexpressed in breast cancer-derived cell lines and in both precancerous breast lesions and advanced primary human breast cancers, suggesting that Par6 overexpression regulates tumor initiation and progression. Thus, in addition to regulating cell polarization processes, Par6 is an inducer of cell proliferation in breast epithelial cells.
| Item Type: | Paper |
|---|---|
| Additional Information: | t, Non-P.H.S. |
| Uncontrolled Keywords: | Adaptor Proteins, Signal Transducing/analysis/*physiology Breast Neoplasms/chemistry/*pathology Cell Line, Tumor Cell Polarity Cell Proliferation Epidermal Growth Factor/physiology Extracellular Signal-Regulated MAP Kinases/metabolism Female Humans MAP Kinase Signaling System Phosphorylation Precancerous Conditions/chemistry/pathology Protein Kinase C/physiology Receptors, Estrogen/analysis cdc42 GTP-Binding Protein/physiology |
| Subjects: | diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification diseases & disorders > cancer > cancer types > breast cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Muthuswamy lab |
| Depositing User: | Matt Covey |
| Date: | 15 October 2008 |
| Date Deposited: | 25 Feb 2013 21:23 |
| Last Modified: | 25 Feb 2013 21:23 |
| PMCID: | PMC2948755 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27594 |
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