Endocrine Abstracts

The androgen receptor (AR) is a major therapeutic target once prostate cancer has progressed. Even invasive cells remain initially responsive to androgen deprivation therapy (ADT) but ultimately become ADT-recurrent, which is lethal. Aggressive ADT-recurrent cells nonetheless retain active AR signaling, but in a distorted form as a result of the actions of transcription factor co-regulators, including the corepressors, for example as revealed by the TCGA consortium. We have examined how corepressors distort AR signaling in prostate cancer progression by determining the choice and capacity of AR binding. Combining ChIP approaches with TCGA data revealed that NCOR1 and NCOR2/SMRT have altered interactions with the AR in cell models of different stages of disease, and led to altered DNA CpG methylation in tumors. Genome-wide ChIP-Seq approaches established the NCOR1 and NCOR2/SMRT cistrome in AR sensitive and ADT-recurrent models. An integrative genomic pipeline revealed that the choice of binding site and the effect of gene expression was extremely dynamic. Notably, distal NCOR2/SMRT binding significantly associated with gene repression. In ADT-sensitive models, activation of the AR receptor induced the NCOR2/SMRT to proximal binding where it was more frequently associated with elevated gene expression. Interestingly, basal NCOR2/SMRT distribution in ADT-recurrent models reflected the patterns in ADT-sensitive models following AR stimulation. These findings suggest that the NCOR2/SMRT function is distorted in ADT models to phenocopy the effect of AR stimulation. Supporting a pro-tumorgenic role, NCOR2/SMRT staining on a TMA of 600 men following radical prostatectomy revealed that elevated co-repressor staining was associated with several poor outcome measures including time to treatment failure. Thus NCOR2/SMRT elevation may play a role to enhance AR actions in aggressive cancers and associates with worse disease outcome.