SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation
- 29 February 2016
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 76 (5), 1112-1121
- https://doi.org/10.1158/0008-5472.can-15-1868
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. Cancer Res; 76(5); 1112–21. ©2015 AACR.Keywords
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This publication has 42 references indexed in Scilit:
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancerProceedings of the National Academy of Sciences of the United States of America, 2011
- Molecular genetics of prostate cancer: new prospects for old challengesGenes & Development, 2010
- Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitorsNature Communications, 2010
- Outcomes of Localized Prostate Cancer Following Conservative ManagementJama-Journal Of The American Medical Association, 2009
- The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer†Human Molecular Genetics, 2009
- Tenets of PTEN Tumor SuppressionCell, 2008
- Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinomaProceedings of the National Academy of Sciences of the United States of America, 2008
- Endogenous human microRNAs that suppress breast cancer metastasisNature, 2008
- GenePattern 2.0Nature Genetics, 2006