title: Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression.
abstract: Castration therapy in advanced prostate cancer eventually fails and leads to the development of castration-resistant prostate cancer (CRPC), which has no cure. Characteristic features of CRPC can be increased androgen receptor (AR) expression and altered transcriptional output. We investigated the expression of nuclear receptor corepressor 1 (NCOR1) in human prostate and prostate cancer and the role of NCOR1 in response to antiandrogens.
  
  
  
  NCOR1 protein levels were compared between matched normal prostate and prostate cancer in 409 patient samples. NCOR1 knockdown was used to investigate its effect on bicalutamide response in androgen-dependent prostate cancer cell lines and transcriptional changes associated with the loss of NCOR1. NCOR1 transcriptional signature was also examined in prostate cancer gene expression datasets.
  
  
  
  NCOR1 protein was detected in cytoplasm and nuclei of secretory epithelial cells in normal prostate. Both cytoplasmic and nuclear NCOR1 protein levels were lower in prostate cancer than in normal prostate. Prostate cancer metastases show significant decrease in NCOR1 transcriptional output. Inhibition of LNCaP cellular proliferation by bicalutamide requires NCOR1. NCOR1-regulated genes suppress cellular proliferation and mediate bicalutamide resistance. In the mouse, NCOR1 is required for bicalutamide-dependent regulation of a subset of the AR target genes.
  
  
  
  In summary, we demonstrated that NCOR1 function declines with prostate cancer progression. Reduction in NCOR1 levels causes bicalutamide resistance in LNCaP cells and compromises response to bicalutamide in mouse prostate in vivo Clin Cancer Res; 22(15); 3937-49. ©2016 AACR.
authors.affiliation: Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida. Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Lopez
authors.affiliation: Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Agoulnik
authors.affiliation: Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida.
authors.forename: Manqi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Center for Biostatistics, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Leif E
authors.initials: LE
authors.lastname: Peterson
authors.affiliation: Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida.
authors.forename: Egla
authors.initials: E
authors.lastname: Suarez
authors.affiliation: Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Gandarillas
authors.affiliation: Dan L. Duncan Cancer Center-Biostatistics, Baylor College of Medicine, Houston, Texas.
authors.forename: Anna
authors.initials: A
authors.lastname: Frolov
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Rile
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Kimal
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Christian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas. Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
authors.affiliation: Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. Biomolecular Sciences Institute, School of Integrated Science and Humanity, Florida international University, Miami, Florida. Irina.Agoulnik@fiu.edu.
authors.forename: Irina U
authors.initials: IU
authors.lastname: Agoulnik
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D034622:RNA Interference; D014105:Tosyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D059467:Transcriptome
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; C539127:NCOR1 protein, human; D009570:Nitriles; D056971:Nuclear Receptor Co-Repressor 1; D014105:Tosyl Compounds; C053541:bicalutamide