title: 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.affiliation: Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Helen B
authors.initials: HB
authors.lastname: Pearson
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Perez-Mancera
authors.forename: Lukas E
authors.initials: LE
authors.lastname: Dow
authors.forename: Andrew
authors.initials: A
authors.lastname: Ryan
authors.forename: Pierre
authors.initials: P
authors.lastname: Tennstedt
authors.forename: Debora
authors.initials: D
authors.lastname: Bogani
authors.forename: Imogen
authors.initials: I
authors.lastname: Elsum
authors.forename: Andy
authors.initials: A
authors.lastname: Greenfield
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Humbert
mesh_terms: D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D018450:Disease Progression; D055786:Gene Knockout Techniques; D011905:Genes, ras; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019048:Prostatic Intraepithelial Neoplasia / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; C480591:SCRIB protein, human; C508433:scrib protein, mouse