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.