Role of the TMPRSS2-ERG gene fusion in prostate cancer

Scott A. Tomlins, Bharathi Laxman, Sooryanarayana Varambally, Xuhong Cao, Jindan Yu, Beth E. Helgeson, Qi Cao, John R. Prensner, Mark A. Rubin, Rajal B. Shah, Rohit Mehra, Arul M. Chinnaiyan*

*Corresponding author for this work

Research output: Contribution to journalArticle

446 Scopus citations

Abstract

TMPRSS2-ERG gene fusions are the predominant molecular subtype of prostate cancer. Here, we explored the role of TMPRSS2-ERG gene fusion product using in vitro and in vivo model systems. Transgenic mice expressing the ERG gene fusion product under androgen-regulation develop mouse prostatic intraepithelial neoplasia (PIN), a precursor lesion of prostate cancer. Introduction of the ERG gene fusion product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did not increase cellular proliferation or anchorage-independent growth. These results suggest that TMPRSS2-ERG may not be sufficient for transformation in the absence of secondary molecular lesions. Transcriptional profiling of ERG knockdown in the TMPPRSS2-ERG-positive prostate cancer cell line VCaP revealed decreased expression of genes over-expressed in prostate cancer versus PIN and genes overexpressed in ETS-positive versus -negative prostate cancers in addition to inhibiting invasion. ERG knockdown in VCaP cells also induced a transcriptional program consistent with prostate differentiation. Importantly, VCaP cells and benign prostate cells overexpressing ERG directly engage components of the plasminogen activation pathway to mediate cellular invasion, potentially representing a downstream ETS target susceptible to therapeutic intervention. Our results support previous work suggesting that TMPRSS2-ERG fusions mediate invasion, consistent with the defining histologic distinction between PIN and prostate cancer.

Original languageEnglish (US)
Pages (from-to)177-188
Number of pages12
JournalNeoplasia
Volume10
Issue number2
DOIs
StatePublished - Feb 2008

ASJC Scopus subject areas

  • Cancer Research

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    Tomlins, S. A., Laxman, B., Varambally, S., Cao, X., Yu, J., Helgeson, B. E., Cao, Q., Prensner, J. R., Rubin, M. A., Shah, R. B., Mehra, R., & Chinnaiyan, A. M. (2008). Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia, 10(2), 177-188. https://doi.org/10.1593/neo.07822