Abstract 944: Glucocorticoid receptor (GR)-mediated activation of cyclic-adenosine monophosphate (cAMP) pathway gene expression following androgen receptor (AR) antagonism of prostate cancer
Authors: Long Tiha M. , Tonsing-Carter Eva Y. , Chan Wen-Ching , Griend Donald Vander , Conzen Suzanne D. , Szmulewitz Russell Z. 
Published: August 2018

Background: Despite the recent discovery of several potent androgen receptor (AR)-targeted therapies, progressive castration-resistant prostate cancer (CRPC) remains the second leading cause of male cancer deaths in the United States. While androgen-deprivation therapy (ADT) and AR antagonism continue to be the standard of care for progressive metastatic CRPC, identifying alternative molecular mechanisms is crucial. Our lab and others have shown that increased glucocorticoid receptor (GR) expression and activity can contribute to CRPC progression; this discovery has led to the development of selective GR modulators (SGRMs) as potential therapies for CRPC. Although GR clearly contributes to cell growth in AR-blocked PC cells, it is unclear whether GR serves solely to recapitulate AR-driven cancer-related mechanisms or if GR also regulates critical gene expression pathways unique to GR (and different from AR) allowing a novel growth advantage for tumor cells.

Methods: Primary PC and metastatic CRPC samples were normalized and utilized for gene expression analysis. LAPC4 and CWR-22Rv1 PC cell lines were treated with androgen +/- enzalutamide +/- dexamethasone and +/- SGRMs in order to activate or inhibit GR function in both AR active and AR-blocked conditions. For transcriptome analysis we performed next generation sequencing (NGS) of RNA followed by gene expression pathway analysis. To determine GR and AR chromatin binding sites, we performed GR and AR ChIP followed by DNA NGS.

Results: Transcriptome analysis of GR-mediated gene expression in LAPC4 PC cells following AR antagonism revealed that the majority of GR-regulated genes were unique to GR activity rather than overlapping with AR target genes.. Furthermore, GR and AR ChIP-sequencing indicated that while important overlap existed between GR and AR ChIP-seq, the majority of GR binding sites were distinct from AR binding sites. Analysis of the GR-unique transcriptomes of both enzalutamide-treated LAPC4 and CWR-22Rv1 cells predicted that cAMP-mediated signaling was activated by GR. Antagonism of GR with SGRMs blocked GR-unique cAMP pathway gene expression. Gene expression analysis of patient samples indicated that GR signaling is also activated in mCRPC and correlated with increased cAMP pathway gene expression.

Conclusions: These data suggest that GR activity in progressive CRPC results in novel GR-specific mechanisms of CRPC progression involving signaling pathways distinct from those driven by AR activation.

Citation Format: Tiha M. Long, Eva Y. Tonsing-Carter, Wen-Ching Chan, Donald Vander Griend, Suzanne D. Conzen, Russell Z. Szmulewitz. Glucocorticoid receptor (GR)-mediated activation of cyclic-adenosine monophosphate (cAMP) pathway gene expression following androgen receptor (AR) antagonism of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 944.