SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia.
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SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. / Pearson, Helen B; Perez-Mancera, Pedro A; Dow, Lukas E; Ryan, Andrew; Tennstedt, Pierre; Bogani, Debora; Elsum, Imogen; Greenfield, Andy; Tuveson, David A; Simon, Ronald; Humbert, Patrick O.
in: J CLIN INVEST, Jahrgang 121, Nr. 11, 11, 2011, S. 4257-4267.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia.
AU - Pearson, Helen B
AU - Perez-Mancera, Pedro A
AU - Dow, Lukas E
AU - Ryan, Andrew
AU - Tennstedt, Pierre
AU - Bogani, Debora
AU - Elsum, Imogen
AU - Greenfield, Andy
AU - Tuveson, David A
AU - Simon, Ronald
AU - Humbert, Patrick O
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Male
KW - Disease Progression
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - Mutation
KW - Base Sequence
KW - Genes, ras
KW - Heterozygote
KW - MAP Kinase Signaling System
KW - Kaplan-Meier Estimate
KW - Tissue Array Analysis
KW - RNA, Messenger/genetics/metabolism
KW - Gene Knockout Techniques
KW - Intracellular Signaling Peptides and Proteins/deficiency/genetics
KW - Membrane Proteins/genetics/metabolism
KW - Prostatic Intraepithelial Neoplasia/etiology/genetics/metabolism/pathology
KW - Prostatic Neoplasms/etiology/genetics/metabolism/pathology
KW - RNA, Neoplasm/genetics/metabolism
KW - Tumor Suppressor Proteins/genetics/metabolism
KW - Animals
KW - Humans
KW - Male
KW - Disease Progression
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - Mutation
KW - Base Sequence
KW - Genes, ras
KW - Heterozygote
KW - MAP Kinase Signaling System
KW - Kaplan-Meier Estimate
KW - Tissue Array Analysis
KW - RNA, Messenger/genetics/metabolism
KW - Gene Knockout Techniques
KW - Intracellular Signaling Peptides and Proteins/deficiency/genetics
KW - Membrane Proteins/genetics/metabolism
KW - Prostatic Intraepithelial Neoplasia/etiology/genetics/metabolism/pathology
KW - Prostatic Neoplasms/etiology/genetics/metabolism/pathology
KW - RNA, Neoplasm/genetics/metabolism
KW - Tumor Suppressor Proteins/genetics/metabolism
M3 - SCORING: Journal article
VL - 121
SP - 4257
EP - 4267
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 11
M1 - 11
ER -
