title: Characterisations of human prostate stem cells reveal deficiency in class I UGT enzymes as a novel mechanism for castration-resistant prostate cancer.
abstract: BACKGROUND
  Evidence increasingly supports that prostate cancer is initiated by the malignant transformation of stem cells (SCs). Furthermore, many SC-signalling pathways are shown to be shared in prostate cancer. Therefore, we planned transcriptome characterisation of adult prostate SCs as a strategy to consider new targets for cancer treatment.
  
  
  METHODS
  Intuitive pathway analysis was used for putative target discovery in 12 matched selections of human prostate SCs, transiently amplifying cells and terminally differentiated cells. These were pooled into three groups according to the stage of differentiation for mRNA microarray analysis. Targets identified were validated using uncultured primary tissue (n=12), functional models of prostate cancer and a tissue microarray consisting of benign (n=42) and malignant prostate (n=223).
  
  
  RESULTS
  A deficiency in class 1 UDP glucuronosyltransferase (UGT) enzymes (UGT1A) was identified in prostate SCs, which are involved in androgen catabolism. Class 1 UGT enzyme expression was also downregulated in cancer SCs and during progression to metastatic castration-resistant prostate cancer (CRPC). Reduction of UGT1A expression in vitro was seen to improve cell survival and increase androgen receptor (AR) activity, as shown by upregulation of prostate-specific antigen expression.
  
  
  CONCLUSIONS
  Inactivation of intracellular androgen catabolism represents a novel mechanism to maintain AR activity during CRPC.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, NE2 4HH, Newcastle upon Tyne United Kingdom.
authors.forename: S C
authors.initials: SC
authors.lastname: Williamson
authors.forename: R
authors.initials: R
authors.lastname: Mitter
authors.forename: A C
authors.initials: AC
authors.lastname: Hepburn
authors.forename: L
authors.initials: L
authors.lastname: Wilson
authors.forename: A
authors.initials: A
authors.lastname: Mantilla
authors.forename: H Y
authors.initials: HY
authors.lastname: Leung
authors.forename: C N
authors.initials: CN
authors.lastname: Robson
authors.forename: R
authors.initials: R
authors.lastname: Heer
mesh_terms: D053687:Adult Stem Cells / Q000201:enzymology*; D000728:Androgens / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D008297:Male; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D011467:Prostate / Q000166:cytology / Q000201:enzymology*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D059467:Transcriptome; D015854:Up-Regulation; D000099148:UGT1A1 Enzyme
chemical_list: D000728:Androgens; D014453:Glucuronosyltransferase; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D012333:RNA, Messenger; D011944:Receptors, Androgen; D000099148:UGT1A1 Enzyme; C549870:KLK3 protein, human