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.
authors.affiliation: Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Bharathi
authors.initials: B
authors.lastname: Laxman
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Jindan
authors.initials: J
authors.lastname: Yu
authors.forename: Beth E
authors.initials: BE
authors.lastname: Helgeson
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Rajal B
authors.initials: RB
authors.lastname: Shah
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D050939:Gene Fusion; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010960:Plasminogen Activators / Q000378:metabolism; D011467:Prostate / Q000166:cytology; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
chemical_list: D004268:DNA-Binding Proteins; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D010960:Plasminogen Activators