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Revision as of 17:46, 24 March 2010
Androgens, functioning through androgen receptor (AR), are essential for the initiation and progression of prostate cancer. Thus androgen-ablation therapies, which involve surgical castration or the use of luteinizing hormone-releasing hormone (LHRH) agonists (or antagonists), have been the mainstay of treatment for advanced androgen-dependent prostate cancer (ADPCa) for over 40 years. While such therapies initially lead to disease regression, in general, advanced prostate cancer ultimately progresses to an androgen-independent prostate cancer (AIPCa) late stage that is refractory to current therapies. My laboratory is interested in understanding the molecular pathological mechanisms underlying the development and progression of prostate cancer. As AR is expressed in the vast majority of both ADPCa and AIPCa, and decreasing levels of AR protein expression reduces both ADPCa and AIPCa growth in model systems, it appears AR signaling pathways play a critical role in both ADPCa and AIPCa.
AR is a ligand-dependent transcription factor belonging to the nuclear hormone receptor (NR) superfamily. The application of chromatin immunoprecipitation (ChIP) to study protein-DNA interaction has provided a wealth of information on temporal and spatial assembly of AR transcription complex on target gene regulatory regions in vivo. However, studying of only a few target genes by ChIP greatly limits our understanding of how AR regulates target gene network. The recent development of the ChIP-on-chip (ChIP on a microarray) or ChIP-seq (ChIP combined with high throughput sequencing) technique allows the global identification of specific transcription factor regulatory regions across the human genome. Recently, we have mapped AR binding regions in the entire human genome in ADPCa and AIPCa. By combining the AR binding maps with gene expression profiles, we have begun to understand how AR regulates target gene networks in ADPCa and AIPCa. Currently, we are extending our view from transcriptional regulation by AR to wider transcriptional regulations in prostate cancer including studying combinatorial transcriptional regulation by AR, its collaborating transcription factors, and its coactivators. We will also apply the genome-wide ChIP technique to clinical samples obtained from different stages of prostate cancer. This would allow identification of critical cis-regulatory sequences contributing to prostate cancer progression.