Gene profiling in transurethral resection samples of patients with hormone-refractory prostate cancer (HRPC)

Abstract

4641 Background: Patients with metastatic carcinoma of the prostate (CaP) develop after a mean of 15 months resistance to hormone ablation therapy. However, the underlying molecular mechanisms are still unknown. Our goal was to identify the transcriptional changes that are characteristic for the transition to hormone resistant prostate cancer (HRPC) using oligonucleotide microarrays. Here, we report the attempt to profile fresh frozen tissue obtained by palliative transurethral resection (TUR) in patients with HRPC and concomittant urinary obstruction. Methods: Indications for palliative TUR were locally progressive tumors with obstruction and voiding problems. HRPC was defined according to the criteria of Scher et al. 1995. Samples of 8 HRPC patients were compared to tissues from 8 hormone-sensitive CaP patients including biological and technical replicates. All tissue samples had been pathologically evaluated. Only macrodissected prostate samples with at least 70% tumor content were used for RNA extraction. RNA quality was controlled using the Bioanalyzer Nanochip (Agilent Technologies, Palo Alto). Expression analysis was performed on Affymetrix oligonucleotide arrays. Results: We identified 323 genes being significantly deregulated (corrected p-value <0.05, false discovery rate <0.05). These genes were mapped to cellular pathways using the KEGG annotation and the most significantly deregulated pathways were identified. Deregulation of metabolic pathways included fatty acid metabolism as well as oxidative phosphorylation and ATP synthesis. Cell cycle control seems to be further suppressed by the downregulation of JNK-pathway via MEKK4 and JUND, the downregulation of p21 (CDKN1A) and the induction of Cylcin D1. We also present evidence for a significant downregulation of actin cyctoskeleton components. Deregulated genes likely to be specific for the transition from prostate carcinoma to HRPC will be presented. Conclusions: Gene expression profiling has been successfully standardised using fresh TUR material of HRPC patients. Deregulated genes have been mapped to specific signal transduction pathways. On this platform, clinical trials in patients with HRPC using specific inhibitors of cell signalling are being developed. [Table: see text]