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      ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

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          Abstract

          The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoid acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits coactivators SRC-1 and -3 to an AR-RORE to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR gene network. Lastly, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing but not AR-negative xenograft PCa models, and effectively sensitized CRPC tumors to enzalutamide, without overt toxicity in mice. Together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and a potential therapeutic target for advanced PCa.

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          Most cited references 47

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          Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

          The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.
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            The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man.

            The androgen receptor (AR) regulates prostate cell growth in man, and prostate cancer is the commonest cancer in men in the UK. We present a comprehensive analysis of AR binding sites in human prostate cancer tissues, including castrate-resistant prostate cancer (CRPC). We identified thousands of AR binding sites in CRPC tissue, most of which were not identified in PC cell lines. Many adjacent genes showed AR regulation in xenografts but not in cultured LNCaPs, demonstrating an in-vivo-restricted set of AR-regulated genes. Functional studies support a model of altered signaling in vivo that directs AR binding. We identified a 16 gene signature that outperformed a larger in-vitro-derived signature in clinical data sets, showing the importance of persistent AR signaling in CRPC. Copyright © 2013 Elsevier Inc. All rights reserved.
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              REV-ERB and ROR nuclear receptors as drug targets.

              The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiological processes, including regulation of metabolism, development and immunity as well as the circadian rhythm. The recent characterization of endogenous ligands for these former orphan nuclear receptors has stimulated the development of synthetic ligands and opened up the possibility of targeting these receptors to treat several diseases, including diabetes, atherosclerosis, autoimmunity and cancer. This Review focuses on the latest developments in ROR and REV-ERB pharmacology indicating that these nuclear receptors are druggable targets and that ligands targeting these receptors may be useful in the treatment of several disorders.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                16 March 2016
                28 March 2016
                May 2016
                01 November 2016
                : 22
                : 5
                : 488-496
                Affiliations
                [1 ]Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California, USA
                [2 ]Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou, China
                [3 ]Department of Urology, School of Medicine, University of California, Davis, California, USA
                [4 ]Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California, USA
                [5 ]Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, California, USA
                [6 ]Shantou University Medical College, No. 22 Xinling Road, Shantou, China
                [7 ]Gene Expression Laboratory, Salk Institute, Howard Hughes Medical Institute, Salk Institute, La Jolla, California, USA
                [8 ]Comprehensive Cancer Center, School of Medicine, University of California, Davis, Sacramento, California, USA
                Author notes
                Correspondence should be addressed to H-W.C. ( hwzchen@ 123456ucdavis.edu ) or Y.X. ( xu_yong@ 123456gibh.ac.cn )
                Article
                NIHMS762028
                10.1038/nm.4070
                5030109
                27019329

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