SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

Pearson, H. B., Perez-Mancera, P. A., Dow, L. E., Ryan, A., Tennstedt, P., Bogani, D., Elsum, I., Greenfield, A., Tuveson, D. A., Simon, R., Humbert, P. O. (2011) SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. Journal of Clinical Investigation, 121 (11). pp. 4257-4267. ISSN 0021-9738

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URL: http://www.ncbi.nlm.nih.gov/pubmed/21965329
DOI: 10.1172/jci58509

Abstract

Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention.

Item Type: Paper
Additional Information:
Uncontrolled Keywords: tumor-suppressor scribble ubiquitin-mediated degradation papillomavirus e6 proteins cell polarity epithelial-cells growth-factor discs large k-ras mouse progression
Subjects: bioinformatics
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
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types

organs, tissues, organelles, cell types and functions > cell types and functions
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell

organs, tissues, organelles, cell types and functions
diseases & disorders > cancer > cancer types > prostate cancer
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 07 Feb 2013 16:54
Last Modified: 07 Feb 2013 16:54
PMCID: PMC3223862
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27118

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