Endocrine Abstracts

Prostate cancer is an androgen dependent malignancy that initially responds well to androgen ablation therapy. However treatment, castrate resistant prostate cancer eventually emerges. Even in that phase of the disease, the androgen receptor (AR) still seems to play a role. MicroRNAs are small (19–25nt) non-coding RNAs that modulate gene silencing through inhibition of translation and mRNA degradation. They are considered to be master regulators of gene expression and act both as oncogenes and tumour suppressors, as well as possible biomarkers and therapeutic targets for prostate cancer. We have identified a number of miRs that modulate AR activity in AR-dependent and castrate resistant cell lines and may have roles in human progression. We have investigated the effect of miR modulation on AR activity and identified pathways that could be used as possible therapeutic targets in hormone unresponsive prostate cancer. Prostate cancer cell lines that stably expressed an AR reporter element were transfected with specific miR inhibitors and mimics. We investigated the effect of miR modulation on potential alteration in AR activity (through a luciferase assay), on cell growth by an SRB assay and on apoptosis, using a caspase 3/7 assay on AR-dependent and castrate resistant cell lines. Of three miRs tested, two mimics significantly increased AR activity in the castrate resistant cell line and one inhibitor significantly reduced AR activity in the castrate resistant cell line. In cell growth assays, an inhibitor of one of these miRs reduced growth of the AR dependent cell line. For two miRs, mimic increased while inhibitor repressed AR activity and growth, suggesting they are potential oncomiRs in prostate cancer. Predicted targets include genes with roles in growth arrest, apoptosis or DNA repair. Future studies will be directed towards further characterisation of those miRs, through alteration of mRNA and protein levels of AR and AR target genes.

Presenting author: Foteini Kalofonou, Division of Cancer, Department of Surgery and Cancer, Imperial Centre for Translational & Experimental Medicine, Imperial College London, Hammersmith Hospital Campus London W12 0NN, UK. Email: [email protected].