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

Pearson, Helen B. ORCID: https://orcid.org/0000-0002-3284-0843, Perez-Mancera, Pedro A., Dow, Lukas E., Ryan, Andrew, Tennstedt, Pierre, Bogani, Debora, Elsum, Imogen, Greenfield, Andy, Tuveson, David A., Simon, Ronald and Humbert, Patrick O. 2011. SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. The Journal of Clinical Investigation 121 (11) , pp. 4257-4267. 10.1172/JCI58509

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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:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	American Society for Clinical Investigation
ISSN:	0021-9738
Date of First Compliant Deposit:	3 April 2019
Date of Acceptance:	16 August 2011
Last Modified:	02 Jul 2023 19:05
URI:	https://orca.cardiff.ac.uk/id/eprint/105959

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