Identification of androgen receptor (AR) target genes putatively involved in the emergence of hormone-refractory prostate cancer

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Androgen receptor (AR) is known to have an important role in prostate cancer (PC) progression from hormone-sensitive to hormone-refractory disease. Overexpression of AR is found in a majority of the hormone-refractory PC (HR-PC) and several AR target genes have been identified. However, which of the target genes are the most important and responsible for prostate cancer progression is still unsolved.
 Our goal was to find significant androgen and AR regulated target genes for prostate cancer progression to the hormone-refractory state. Parental LNCaP cells transfected with AR (LNCaP-moAR and LNCaP-hiAR) or with empty transfection cassette (LNCaP-pcDNA3.1) as well as VCaP cells, containing an endogenous AR-amplification, were treated with 0, 0.1nM, 1nM, 10nM or 100nM DHT (dihydrotestosterone) for 4h and 24h. Treatments were validated by measuring the induction of PSA (Prostate Specific Antigen) that is a well known AR target gene.
 The highest AR-overexpressing LNCaP model (LNCaP-hiAR) gained growth benefit in low androgen levels compared to the model expressing AR moderately (LNCaP-moAR) or empty pcDNA3.1 carrying control LNCaP cells. According to our preliminary results of ongoing analysis with Illumina humanRef-8 v2 beadchips, the amount of differently regulated genes increases with AR level, and the higher AR amount in the cells sensitizes the expression of AR up-regulated genes. Using clustering analysis three main differently up-regulated subgroups in both 4h and 24h can be distinguished. Interestingly, one of those includes many genes involved in the cell cycle and DNA metabolism as well as chromosomal rearrangement. Since the expression profile of genes involved in cell cycle and DNA-metabolism fits well with the growth data of the AR-model, we expect to find the most interesting AR up-regulated target genes in that particular subgroup.