title: Dominant-negative androgen receptor inhibition of intracrine androgen-dependent growth of castration-recurrent prostate cancer.
abstract: BACKGROUND
  Prostate cancer (CaP) is the second leading cause of cancer death in American men. Androgen deprivation therapy is initially effective in CaP treatment, but CaP recurs despite castrate levels of circulating androgen. Continued expression of the androgen receptor (AR) and its ligands has been linked to castration-recurrent CaP growth.
  
  
  RESULTS
  In this report, the ligand-dependent dominant-negative ARΔ142-337 (ARΔTR) was expressed in castration-recurrent CWR-R1 cell and tumor models to elucidate the role of AR signaling. Expression of ARΔTR decreased CWR-R1 tumor growth in the presence and absence of exogenous testosterone (T) and improved survival in the presence of exogenous T. There was evidence for negative selection of ARΔTR transgene in T-treated mice. Mass spectrometry revealed castration-recurrent CaP dihydrotestosterone (DHT) levels sufficient to activate AR and ARΔTR. In the absence of exogenous testosterone, CWR-R1-ARΔTR and control cells exhibited altered androgen profiles that implicated epithelial CaP cells as a source of intratumoral AR ligands.
  
  
  CONCLUSIONS
  The study provides in vivo evidence that activation of AR signaling by intratumoral AR ligands is required for castration-recurrent CaP growth and that epithelial CaP cells produce sufficient active androgens for CaP recurrence during androgen deprivation therapy. Targeting intracrine T and DHT synthesis should provide a mechanism to inhibit AR and growth of castration-recurrent CaP.
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Titus
authors.forename: Brian
authors.initials: B
authors.lastname: Zeithaml
authors.forename: Boris
authors.initials: B
authors.lastname: Kantor
authors.forename: Xiangping
authors.initials: X
authors.lastname: Li
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.forename: Dominic T
authors.initials: DT
authors.lastname: Moore
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.forename: Tal
authors.initials: T
authors.lastname: Kafri
mesh_terms: D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone