SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia
Helen B. Pearson, Pedro A. Perez-Mancera, Lukas E. Dow, Andrew Ryan, Pierre Tennstedt, Debora Bogani, Imogen Elsum, Andy Greenfield, David A. Tuveson, Ronald Simon, Patrick O. Humbert
Helen B. Pearson, Pedro A. Perez-Mancera, Lukas E. Dow, Andrew Ryan, Pierre Tennstedt, Debora Bogani, Imogen Elsum, Andy Greenfield, David A. Tuveson, Ronald Simon, Patrick O. Humbert
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Research Article Oncology

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

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.

Authors

Helen B. Pearson, Pedro A. Perez-Mancera, Lukas E. Dow, Andrew Ryan, Pierre Tennstedt, Debora Bogani, Imogen Elsum, Andy Greenfield, David A. Tuveson, Ronald Simon, Patrick O. Humbert

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Figure 1

Generation and analysis of Scrib-deficient mice.

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Generation and analysis of Scrib-deficient mice. (A) Schematic repre...
(A) Schematic representation of the WT Scrib allele, targeting construct, and mutated Scrib allele. Excision of the Frt-flanked PGK-Neo cassette in the LoxP-flanked targeting vector was accomplished by crossing Scribfl-Neo mice to Actin-FLPe mice, producing the Scrib floxed (Scribfl) allele. The insertion of EcoRV and KpnI restriction sites permitted screening for recombinant ES cell clones (see Supplemental Figure 1, A and B). Scrib-KO mice were derived by crossing Scrib+/fl mice with a germline Cre-deleter mouse. Exons are indicated as boxes and LoxP/FLPe sites as triangles. (B) Photographs of WT, Scrib+/–, and KO E14.5 embryos. Scale bar: 10 mm. (C) Western blot analysis of embryonic brain lysates (E16.5) confirmed Scrib loss in Scrib+/– and KO compared with WT embryos.