TMPRSS2/ERG fusion gene expression alters chemo- and radio-responsiveness in cell culture models of androgen independent prostate cancer.

ABSTRACT

PURPOSE/OBJECTIVES: The androgen regulated transmembrane serine protease (TMPRSS2) and ETS transcription factor (ERG) gene fusion is a strong prognostic factor for disease recurrence following prostatectomy. Expression of TMPRSS2/ETS-related gene (ERG) fusion gene transcripts is linked with tumor proliferation, invasion, and an aggressive phenotype. The aim of this study was to define the effect of TMPRSS2/ERG fusion gene expression on chemo- and radiosensitivity in prostate tumor cell lines. MATERIALS/METHODS: Clonogenic survival of PC3 and DU145 cells stably expressing TMPRSS2/ERG Types III and VI fusion genes was measured after X-irradiation (0-8 Gy) and Paclitaxel. Cell cycle changes and DNA double-strand break induction and repair were assessed. Differential gene expression was measured by microarray analysis. ERG signaling pathway interactions were studied using Ariadne Pathway Studio. RESULTS: Expression of the TMPRSS2/ERG fusions in PC3 cells increased radiation sensitivity and decreased paclitaxel sensitivity. Increased radiosensitivity was associated with persistent DNA breaks 24 hr post-irradiation, down-regulation of genes involved in DNA repair and mitosis and up-regulation of ETV, an ETS transcription factor. However, DU145 Types III and VI demonstrated a different sensitivity phenotype and gene expression changes. Pathway analysis of ERG signaling further illustrated the variation between the PC3 and DU145 cell lines containing TMPRSS2/ERG fusions. CONCLUSIONS: The effect of TMPRSS2/ERG gene fusions had differing effects on radiosensitivity and chemosensitivity depending on cell line and fusion type. Further work is needed with clinical samples to establish whether TMPRSS2/ERG gene fusions affect radio- and chemosensitivity in vivo.