Introduction: Despite the widespread use of prostate specific antigen screening for early detection, prostate cancer remains the second leading cause of cancer related death among men in the US. Metastatic, hormone refractory prostate cancer (HRPCa) is the end stage, lethal form of the disease. Defining the molecular mechanisms underlying the transition of an androgen responsive prostate cancer represents an important clinical problem. Currently, no effective therapies exist for end stage, hormone refractory disease. In this study, we investigated the differentially expressed genes in primary prostate tumor vs. hormone refractory prostate tumor in order to identify potentially important therapeutic targets.

Methods: Formalin fixed paraffin embedded tumor samples from 14 cases (8 primary, chemotherapy-naïve and 6 locally recurrent, hormonal therapy-refractory carcinomas) were analyzed for the whole genome RNA (29,285 transcripts) microarray analysis using Illumina cDNA-mediated annealing, selection, extension and ligation (DASL) process with the HumanHT-12 v4 beadChip (Illumina Inc., San Diego, CA). Additionally, a select number of chemotherapy-predictive (theranostic) biomarkers were analyzed using immunohistochemical methods.

Results: Transcriptome analysis identified 299 genes highly differentially expressed between the primary and recurrent groups (p-value < 0.01, Student's t-test). Using these 299 genes, we performed two dimensional hierarchical clustering and were able to discover 8 clusters corresponding to 5 general patterns: Pattern 1-underexpressed in both groups but more so in recurrent than primary (2 clusters with 28 and 22 genes respectively); Pattern 2-slightly overexpressed in primary and underexpressed or no change in recurrent (1 cluster with 65 genes); Pattern 3-slightly under expressed/ no change in primary and overexpressed in recurrent (1 cluster, 12 genes); Pattern 4-overexpressed in primary and no change in recurrent (1 cluster, 25 genes); Pattern 5 - overexpressed in both groups but more so in recurrent than primary (3 clusters with 58, 32, and 57 genes in each cluster).

Individual gene analysis revealed upregulation of androgen receptor (AR) mRNA in recurrent HRPCa. This was, however, accompanied by a down regulation of regulator of G-protein signaling 2 (RGS2) and ras responsive element binding protein 1 (RREB1). Consistent down regulation of excision repair cross-complementing group 1 (ERCC1) and thymidylate synthase (TS) proteins were also observed in HRPCa.

Conclusion: Up-regulation of AR in HRPCa is associated with down regulation of androgen receptor signaling co-regulators (RGS2 and RREB1), providing a mechanism of androgen-independent activation of AR in HRPCa. Platinum based drugs may have potential benefit in treating of HRPCa due to the down regulation of nucleotide excision repair protein ERCC1, while fluoropyrimidines are potentially beneficial due to the lack of TS protein expression in HRPCa. The heat map derived signature readily distinguishes between prostate cancer specimens from men who were treatment naïve vs. hormone refractory cancers with 5 different expression patterns.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B92.