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Cancer Res. 2016 Mar 1;76(5):1112-21. doi: 10.1158/0008-5472.CAN-15-1868. Epub 2015 Dec 23.

SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation.

Author information

1
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
2
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia. Department of Urology, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia.
3
Winship Cancer Institute, Emory University, Atlanta, Georgia.
4
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia. Hubert Department of Global Health Infectious Diseases, Rollins School of Public Health, Emory University, Atlanta, Georgia.
5
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio.
6
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104/Université de Strasbourg, Illkirch, France.
7
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
8
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia. cmoreno@emory.edu.

Abstract

Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K-AKT-mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K-AKT-mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN/PI3K/AKT pathway in prostate cancer, with potential implications for combination-targeted therapies against both primary and advanced prostate cancers.

PMID:
26701805
PMCID:
PMC4779598
[Available on 2017-03-01]
DOI:
10.1158/0008-5472.CAN-15-1868
[Indexed for MEDLINE]
Free PMC Article

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