SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation

Martin K Thomsen, Laurence Ambroisine, Sarah Wynn, Kathryn S E Cheah, Christopher S Foster, Gabrielle Fisher, Daniel M Berney, Henrik Møller, Victor E Reuter, Peter Scardino, Jack Cuzick, Narasimhan Ragavan, Paras B Singh, Francis L Martin, Christopher M Butler, Colin S Cooper, Amanda Swain, Transatlantic Prostate Group

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Dysregulation of tissue development pathways can contribute to cancer initiation and progression. In murine embryonic prostate epithelia, the transcription factor SOX9 is required for proper prostate development. In this study, we examined a role for SOX9 in prostate cancer in mouse and human. In Pten and Nkx3.1 mutant mice, cells with increased levels of SOX9 appeared within prostate epithelia at early stages of neoplasia, and higher expression correlated with progression at all stages of disease. In transgenic mice, SOX9 overexpression in prostate epithelia increased cell proliferation without inducing hyperplasia. In transgenic mice that were also heterozygous for mutant Pten, SOX9 overexpression quickened the induction of high-grade prostate intraepithelial neoplasia. In contrast, Sox9 attenuation led to a decrease proliferating prostate epithelia cells in normal and homozygous Pten mutant mice with prostate neoplasia. Analysis of a cohort of 880 human prostate cancer samples showed that SOX9 expression was associated with increasing Gleason grades and higher Ki67 staining. Our findings identify SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it promotes tumor cell proliferation.
Original languageEnglish
Pages (from-to)979-87
Number of pages9
JournalCancer Research
Volume70
Issue number3
DOIs
Publication statusPublished - 1 Feb 2010

Keywords

  • Adult
  • Animals
  • Cell Proliferation
  • Epithelium
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Ki-67 Antigen
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • PTEN Phosphohydrolase
  • Prostate
  • Prostatic Neoplasms
  • Reverse Transcriptase Polymerase Chain Reaction
  • SOX9 Transcription Factor
  • Tissue Array Analysis
  • Transcription Factors

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