Splice Variants and Functions of TMPRSS2-ERG Fusion, a Common Genomic Alteration in Prostate Cancer
B Furusato, C Sun, A Dobi, Y Hu, R Thangapazham, A Mohamed, EJ Whitman, D Hawksworth, SH Tan, J Cullen, Y Chen, G Petrovics, T Sreenath, DG McLeod, S Srivastava, IA Sesterhenn. Armed Forces Institute of Pathology, Washington, DC; Walter Reed Army Medical Center, Washington, DC; Center for Prostate Disease Research, Rockville, MD
Background: ERG oncogene is overexpressed in the majority of prostate cancers due to genomic rearrangements placing the ERG gene under the control of the androgen regulated TMPRSS2 promoter. However, the biological functions of ERG in CaP are not well understood. This study was designed to evaluate the function of ERG and to reveal the forms of ERG in human prostate tumors.
Design: ERG was knocked down in TMPRSS2-ERG expressing VCaP cells. Cell proliferation and tumor growth was assayed by in vitro and in vivo models, respectively. Gene expression changes were evaluated by microarray and by quantitative PCR. ERG splice variants were cloned from a Lambda-Zap cDNA library from TMPRSS2-ERG expressing prostate tumors from six patients.
Results: We demonstrated that ERG activates C-MYC oncogene and negatively regulates the expression of prostate differentiation markers in prostate cancer. The predominant form of ERG in human prostate tumors is a novel type (type II) form that lacks DNA binding domain.
Conclusions: The primary consequence of ERG overexpression in prostate tumors is the suppression of prostate differentiation genes. ERG positively regulates C-MYC oncogene contributing to the suppression of differentiated cellular phenotype. Detection of prostate cancer by Type I and II variants in human prostate tissues is superior to the detection of tumors by the TMPRSS2-ERG fusion junction.
Category: Genitourinary (including renal tumors)
Monday, March 9, 2009 1:00 PM
Poster Session II # 113, Monday Afternoon