title: Role of dutasteride in pre-clinical ETS fusion-positive prostate cancer models.
abstract: BACKGROUND
  Androgens play a crucial role in prostate cancer, hence the androgenic pathway has become an important target of therapeutic intervention. Previously we discovered that gene fusions between the 5'-untranslated region of androgen regulated gene TMPRSS2 and the ETS transcription factor family members were present in a majority of the prostate cancer cases. The resulting aberrant overexpression of ETS genes drives tumor progression.
  
  
  METHODS
  Here, we evaluated the expression levels of 5α-reductase isoenzymes in prostate cancer cell lines and tissues. We tested the effect of dutasteride, a 5α-reductase inhibitor, in TMPRSS2-ERG fusion-positive VCaP cell proliferation and cell invasion. We also evaluated the effect of dutasteride on the TMPRSS2-ERG fusion gene expression. Finally, we tested dutasteride alone or in combination with an anti-androgen in VCaP cell xenografts tumor model.
  
  
  RESULTS
  Our data showed that 5α-reductase SRD5A1 and SRD5A3 isoenzymes that are responsible for the conversion of testosterone to DHT, are highly expressed in metastatic prostate cancer compared to benign and localized prostate cancer. Dutasteride treatment attenuated VCaP cell proliferation and invasion. VCaP cells pre-treated with dutasteride showed a reduction in ERG and PSA expression. In vivo studies demonstrated that dutasteride in combination with the anti-androgen bicalutamide significantly decreased tumor burden in VCaP cell xenograft model.
  
  
  CONCLUSIONS
  Our findings suggest that dutasteride can inhibit ERG fusion-positive cell growth and in combination with anti-androgen, significantly reduce the tumor burden. Our study suggests that anti-androgens used in combination with dutasteride could synergistically augment the therapeutic efficacy in the treatment of ETS-positive prostate cancer.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Bushra
authors.initials: B
authors.lastname: Ateeq
authors.forename: Adaikkalam
authors.initials: A
authors.lastname: Vellaichamy
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068538:Dutasteride; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D007527:Isoenzymes; D015514:Oncogene Proteins, Fusion; D012334:RNA, Neoplasm; C529660:TMPRSS2-ETS fusion protein, human; D000068538:Dutasteride