The AR Controls a Tissue-Specific Gene Expression Program in CRPC

Transcriptional regulation by the androgen receptor (AR) promotes prostate cancer growth and is implicated in the progression to castration-resistant prostate cancer (CRPC), which is responsive to AR-targeted therapeutic strategies. However, AR-dependent gene signatures that have been characterized in vitro using cell lines do not accurately refl ect the role of AR signaling in CRPC. To assess whether distinct AR-regulated genes exist in vivo, Sharma and colleagues comprehensively assessed AR-binding sites in a panel of human prostate cancer tissues. Although they observed some overlap with the AR-binding profile in prostate cancer cell lines, which are derived from metastatic tumors, most of the AR-binding sites detected in CRPC were not present in cell lines and were associated with active histone marks at gene promoters. These CRPC-specific AR target genes were not stimulated by androgen in vitro but were downregulated in xenografts and primary prostate tumors following surgical or chemical castration, respectively, defining an in vivo-restricted AR-regulated gene set. Intriguingly, CRPC-specific AR-binding sites did not overlap with motifs for common AR cofactors such as forkhead box A1 (FOXA1) but were instead enriched for E2F, MYC, and STAT motifs, suggesting that altered signaling in CRPC tissue modulates AR activity. Consistent with this idea, AR–FOXA1 interaction was diminished, whereas AR–STAT5 binding was enhanced in prostate cancer cell xenografts compared with isogenic cultured cells, and in vitro treatment with cytokines that stimulate these alternate pathways redirected AR binding to CRPC-specific sites. Furthermore, a core 16-gene CRPC-specific AR signature was tightly correlated with tumor recurrence after hormone therapy and was a better predictor of survival compared with an existing in vitro-derived AR signature. These findings identify potential markers of disease progression and therapeutic response and emphasize the importance of cellular context in the regulation of gene expression programs.

Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD, et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 2013;23:35–47.

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