Abstract Locally advanced and metastatic prostate cancer are treated by hormone ablation therapy. However, despite an initial response, the majority of men relapse within 2–3 years to develop a castrate resistant disease for which there are no effective treatments; therefore defining the mechanisms of resistance represents a significant question. Androgen-independent (AI) sublines were derived from the androgen-dependent (AD) LNCaP cells. Previous studies in our laboratory have shown a complex interplay between changes in pro and anti-apoptotic proteins in the development of this resistance. Manipulating individual genes has only minor alterations in the resistant phenotype so we hypothesise that targeting the central signalling pathways and transcription factors (TFs) would represent a better therapeutic targeting approach. We have undertaken a transciptomic analysis of the LNCaP parental (AD), LNCaP Abl (AI) and Hof (AI) cell lines, using the Affymetrix HG U133 Plus 2.0 GeneChip. Using a combination of correspondence analysis, between group analysis and co-inertia analysis, we have generated a transriptomic profile showing 900 genes associated with androgen resistance. Most importantly, we have predicted a list of TFs including HSF1, CDP, VDR-RXR, SRF and PBX1, which may be responsible for the differential gene expression observed in the AI compared to the AD cells. Taqman validation of 32 genes, including 6 TFs, has confirmed our gene chip results. Further validation of VDR-RXR and SRF activity was performed using luciferase assays. We are currently focusing on SRF, which has recently been associated with prostate cancer development (1). We have confirmed its up-regulation in the AI cell lines by WB. Due to the heterogeneous nature of prostate cancer and the complex changes associated with the development of androgen resistance, the upstream TFs may represent better therapeutic targets to reverse this resistance. Reference 1. Gorlov et al. Prioritizing genes associated with prostate cancer development. BMC Cancer 2010, 10:599 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-278. doi:10.1158/1538-7445.AM2011-LB-278