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SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia
Helen B. Pearson, … , Ronald Simon, Patrick O. Humbert
Helen B. Pearson, … , Ronald Simon, Patrick O. Humbert
Published October 3, 2011
Citation Information: J Clin Invest. 2011;121(11):4257-4267. https://doi.org/10.1172/JCI58509.
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Research Article Oncology

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

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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.

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 3

Elevated Ras/MAPK signaling is required for Scrib-deficient prostate hyperplasia.

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Elevated Ras/MAPK signaling is required for Scrib-deficient prostate hyp...
(A) PCNA IHC shows a significant increase in PCNA-positive cells in Scrib+/– lesions (2.26% ± 0.62%, mean ± SD) compared with WT (0.47% ± 0.09%, P < 0.0001, unpaired t test, 400 days). (B) IHC in Scrib+/– hyperplastic foci revealed aberrant E-cadherin and p-ERM compared with WT tissue. Arrows indicate aberrant expression. Right column: IF to detect Par3 (red) and pan-Dlg (green) shows that these polarity regulators are mislocalized in Scrib+/– prostate hyperplasia compared with WT prostate (400 days). N, normal Scrib+/– tissue; Hyp, hyperplastic Scrib+/– tissue. Arrowheads indicate Par3 accumulation at tight junctions. (C) IHC revealed a significant elevation in p-ERK–positive nuclei in Scrib+/– lesions compared with WT (unpaired t test, 400 days). (D) IHC revealed a significant elevation in p-ELK1–positive nuclei in Scrib+/– lesions compared with WT (unpaired t test, 400 days). (E) Representative H&E images of Scrib+/– prostates administered vehicle or PD0325901 (20 mg/kg, 5 days on, 2 days off for 3 weeks at 230–260 days of age), and p-ERK staining showing efficient MEK inhibition. (F) Scrib+/– prostate weight is significantly decreased upon MEK inhibition (0.30 ± 0.04 g, mean ± SD) compared with administration of vehicle (0.45 g ± 0.08, P = 0.0003, Mann-Whitney U non-parametric test), similar to the level in WT prostate (P = 0.4606, Mann-Whitney U non-parametric t test). Scale bar: 50 μm (larger panels) and 10 μm (insets). Error bars indicate SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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