1429 IN VIVO READOUT OF ANDROGEN RECEPTOR (AR) FUNCTIONAL STATUS IN PRIMARY TUMORS FOR PATIENT STRATIFICATION

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research VIII1 Apr 20101429 IN VIVO READOUT OF ANDROGEN RECEPTOR (AR) FUNCTIONAL STATUS IN PRIMARY TUMORS FOR PATIENT STRATIFICATION Gyorgy Petrovics, Bungo Furusato, Syed Shaheduzzaman, Yongmei Chen, Timothy Nydam, Lakshmi Ravindranath, Amina Ali, Maryanne Vahey, Isabell Sesterhenn, David McLeod, Albert Dobi, and Shiv Srivastava Gyorgy PetrovicsGyorgy Petrovics Rockville, MD More articles by this author , Bungo FurusatoBungo Furusato Washington, DC More articles by this author , Syed ShaheduzzamanSyed Shaheduzzaman Rockville, MD More articles by this author , Yongmei ChenYongmei Chen Rockville, MD More articles by this author , Timothy NydamTimothy Nydam Washington, DC More articles by this author , Lakshmi RavindranathLakshmi Ravindranath Rockville, MD More articles by this author , Amina AliAmina Ali Washington, DC More articles by this author , Maryanne VaheyMaryanne Vahey Silver Spring, MD More articles by this author , Isabell SesterhennIsabell Sesterhenn Washington, DC More articles by this author , David McLeodDavid McLeod Washington, DC More articles by this author , Albert DobiAlbert Dobi Rockville, MD More articles by this author , and Shiv SrivastavaShiv Srivastava Rockville, MD More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1122AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Expression of the ERG proto-oncogene is activated in 50-70% of prostate tumors by AR mediated signals due to the fusion of AR regulated promoters (primarily TMPRSS2 and to a lesser extent SLC45A3 and NDRG1) to the ERG protein coding sequence. Our previous studies of quantitative expression levels of ERG or TMPRSS2-ERG fusion transcripts have noted that relatively low or no ERG expression in prostate tumors significantly associated with progressive disease. Here, we have tested the hypothesis that ERG expression levels in prostate tumor cells reflect AR transcriptional regulatory function in a given biological context of the tumor progression. Therefore, tumors with lower ERG may represent a subset with attenuated AR signaling. METHODS From over 300 radical prostatectomy (RP) specimens archived in the CPDR Biospecimen Bank with 8-13 years follow-up, 40 frozen tissue specimens were selected for this study: 20 with well/moderately differentiated (WD) tumor and less aggressive clinical features, and 20 with poorly differentiated (PD) tumor and more aggressive clinical characteristics, all from patients with no prior androgen ablation treatment. Prostate epithelial cells with tumor and benign morphology were microdissected (LCM) and the extracted RNA was analyzed by GeneChip technology (Affymetrix) after linear amplification. A selected set of known androgen regulated genes was used as in vivo AR readout (androgen receptor function index = ARFI). Correlation of ERG with ARFI and with clinico-pathological parameters was analyzed by conventional statistical approaches. RESULTS Positive regulation of ERG in the TMPRSS2-ERG fusion context by functional androgen signaling was evident in the majority of human prostate tumors, while absence of ERG tightly correlated with deregulated expression of AR target genes. Overall, ERG expression pattern was similar to that of other AR regulated genes. Strikingly low frequency of ERG expression was noted in PD tumor cells (30%) in comparison to WD tumor cells (80%), suggesting for subdued AR function in a significant fraction of tumors with genomic alterations of ERG. CONCLUSIONS By integrating ERG into a panel of defined AR target genes, we developed a cumulative AR Function Index (ARFI), which if validated may have future potential in stratifying patients for targeted therapy on the basis of overall AR functional status in primary tumors. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e551 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gyorgy Petrovics Rockville, MD More articles by this author Bungo Furusato Washington, DC More articles by this author Syed Shaheduzzaman Rockville, MD More articles by this author Yongmei Chen Rockville, MD More articles by this author Timothy Nydam Washington, DC More articles by this author Lakshmi Ravindranath Rockville, MD More articles by this author Amina Ali Washington, DC More articles by this author Maryanne Vahey Silver Spring, MD More articles by this author Isabell Sesterhenn Washington, DC More articles by this author David McLeod Washington, DC More articles by this author Albert Dobi Rockville, MD More articles by this author Shiv Srivastava Rockville, MD More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...