@article{c2240968c2b44103a63f22e6733fddce,
title = "Role of the TMPRSS2-ERG gene fusion in prostate cancer",
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.",
author = "Tomlins, {Scott A.} and Bharathi Laxman and Sooryanarayana Varambally and Xuhong Cao and Jindan Yu and Helgeson, {Beth E.} and Qi Cao and Prensner, {John R.} and Rubin, {Mark A.} and Shah, {Rajal B.} and Rohit Mehra and Chinnaiyan, {Arul M.}",
note = "Funding Information: Abbreviations: MMP, matrix metalloproteinase; mPIN, mouse prostatic intraepithelial neoplasia; OR, odds ratio; PLAT, tissue plasminogen activator; PLAU, urokinase plasminogen activator; PrEC, primary benign prostate epithelial cell; qPCR, quantitative polymerase chain reaction Address all correspondence to: Arul M. Chinnaiyan, MD, PhD, Department of Pathology, University of Michigan Medical School, 1400 E. Medical Center Dr. 5316 CCGC, Ann Arbor, MI 48109-0602. E-mail: arul@umich.edu 1Supported in part by the Department of Defense (PC040517 to R. M., W81XWH-06-1-0224 to A. M. C. and S. V., and PC060266 to J. Y.), the National Institutes of Health (Prostate Cancer Specialized Program of Research Excellence P50CA69568 to A. M. C. and R. B. S. and R01 CA102872 to A. M. C.), the Early Detection Research Network (UO1 CA111275-01 to A. M. C.), and the Prostate Cancer Foundation (to A. M. C.). A. M. C. is supported by a Clinical Translational Research Award from the Burroughs Welcome Foundation. S. A. T. is supported by a Rackham Predoctoral Fellowship. S. A. T. is a Fellow of the Medical Scientist Training Program. 2This article refers to supplementary materials, which are designated by Tables W1, W2, and W3 and Figures W1, W2, W3, W4, W5, W6, W7, and W8 and are available online at www.neoplasia.com. 3Disclosure: The University of Michigan has filed a patent on ETS gene rearrangements and SPINK1 over-expression in prostate cancer, on which S. A. T., R. M., and A. M. C. are co-inventors, and the diagnostic field of use has been licensed to Gen-Probe Incorporated. Gen-Probe also has a sponsored research agreement with A. M. C., however Gen-Probe has not played a role in the design and conduct of the study, in the collection, analysis, or interpretation of the data, and in the preparation, review, or approval of the manuscript. 4S. A. T., B. L., and S. V. contributed equally to this work. Received 5 December 2007; Revised 5 December 2007; Accepted 6 December 2007 Copyright {\textcopyright} 2008 Neoplasia Press, Inc. All rights reserved 1522-8002/08/$25.00 DOI 10.1593/neo.07822",
year = "2008",
month = feb,
doi = "10.1593/neo.07822",
language = "English (US)",
volume = "10",
pages = "177--188",
journal = "Neoplasia",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "2",
}