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  • br Highlights br d ARfl and ARv genomic

    2020-08-04


    Highlights
    d ARfl and ARv7 genomic binding is interdependent and colocalized
    d ARv7, unlike ARfl, preferentially represses transcription
    d Expression of ARv7-repressed Relebactam negatively correlates with recurrence
    d Re-expression of ARv7-repressed genes may serve as a biomarker of ARv7 inhibition
    Cancer Cell Article
    ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer
    6Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard TH Chan School of Public Health, Boston, MA 02215, USA
    7Department of Medicine, University of Washington School of Medicine and GRECC-VAPSHCS, Seattle, WA 98104, USA 8Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany 9Institute of Microstructure Technology, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany 10School of Medicine, Koc¸ University, 34450 Istanbul, Turkey 11Department of Pathology, Erasmus Optical Imaging Centre, Erasmus MC, 3015 GE Rotterdam, the Netherlands 12Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
    13Department of Radiation Oncology, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
    14Department of Urology, Mayo Clinic, Rochester, MN 55905, USA 15Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA 16Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA 17GenomeDx Inc., San Diego, CA 92121, USA 18Vancouver Prostate Center, University of British Columbia, Vancouver, BC V6H 3Z6, Canada 19Present address: Sanofi Oncology, Cambridge, MA 02139, USA 20Present address: EPFL SV GHI LVG, 1015 Lausanne, Switzerland 21Present address: Children’s National Medical Center, Washington, DC 20010, USA 22Present address: Roche Sequencing Solutions, Pleasanton, CA 94588, USA 23Present address: Basilea Pharmaceutica International Ltd., 4005 Basel, Switzerland 24These authors contributed equally 25These authors contributed equally 26Lead Contact *Correspondence: [email protected] (S.R.P.), [email protected] (A.C.G.), [email protected] (M.B.) https://doi.org/10.1016/j.ccell.2019.01.008
    SUMMARY
    Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential bio-markers for tumors dependent on ARv7.
    Significance
    Development of resistance to androgen receptor (AR)-targeted therapy remains a challenge in treating advanced prostate cancer. Our work reveals that the hormone-independent AR splice variant 7 (ARv7) contributes to this process by repressing the transcription of genes with tumor-suppressive activity. Thus, targeting ARv7 may improve currently available prostate cancer therapies by restoring expression of these genes that can serve as biomarkers of ARv7 inhibition.
    INTRODUCTION
    Prostate cancer (PCa) remains one of the most common causes of cancer deaths in men worldwide (Jemal et al., 2011; Siegel et al., 2017). Locally advanced and metastatic PCa is treated with endocrine therapies, aimed at repressing the synthesis of androgens (de Bono et al., 2011; van Poppel and Nilsson, 2008) or at inhibiting androgen receptor (AR) function (Tran et al., 2009). The molecular basis for this therapeutic approach is to block the AR C-terminal, ligand-binding domain (LBD), thereby inhibiting AR-driven oncogenic gene expression pro-grams (Matsumoto et al., 2013; Wang et al., 2009). While this treatment is initially effective, patients frequently develop resis-tance to endocrine therapy and develop castration-resistant PCa (CRPC). CRPC often continues to rely on AR signaling initially (Watson et al., 2015), but the underlying mechanisms of AR reactivation are poorly understood. Proposed mechanisms include genetic alterations of AR (Taplin et al., 1995; Visakorpi et al., 1995) and the expression of truncated, ligand-independent AR variants (AR-Vs), generated via genomic rearrangements and/or alternative splicing events (Dehm et al., 2008; Guo et al., 2009; Hu et al., 2009; Sun et al., 2010).