title: The oncogenic potential of a prostate cancer-derived androgen receptor mutant.
abstract: BACKGROUND
  The role of androgen receptor (AR) mutations in the initiation of prostate cancer (CaP) remains unclear. The purpose of this study was to assess the influence of an AR mutation on prostate tumorigenesis and to determine the resulting molecular alterations.
  
  
  METHODS
  Wild-type AR (AR(WT)) or the CaP-derived K580R AR (AR(K580R)) mutant was stably transfected into SV40-immortalized human prostate epithelial pRNS-1-1 cells that lack AR expression and fail to grow in nude mice. The ability of these AR-transfected cell lines to form tumor was investigated in vitro and in vivo. Additionally, gene expression profiling of these cell lines was performed.
  
  
  RESULTS
  Compared with the AR(WT), the AR(K580R) induced greater than sixfold increase in colony formation in soft agar. In vivo studies confirmed that the AR(K580R)-transfected pRNS-1-1 cells were able to form tumors in nude mice. Using a combination of microarray and RT-PCR, 29 differentially expressed genes were identified in AR(K580R) cells. It was found that silencing the expression of placental alkaline phosphatase (ALPP) that was upregulated in AR(K580R) cells resulted in significant inhibition of cell growth. Furthermore, the AR(K580R)-transfected pRNS-1-1 cells expressed markedly increased p-Akt and p-p70 S6K.
  
  
  CONCLUSIONS
  The AR(K580R) mutation promoted the malignant transformation of prostate epithelial cells. This was associated with upregulation of ALPP and subsequent activation of the Akt signaling pathway.
authors.affiliation: Department of Urology, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
authors.forename: Xu-Bao
authors.initials: XB
authors.lastname: Shi
authors.forename: Lingru
authors.initials: L
authors.lastname: Xue
authors.forename: Clifford G
authors.initials: CG
authors.lastname: Tepper
authors.forename: Regina
authors.initials: R
authors.lastname: Gandour-Edwards
authors.forename: Paramita
authors.initials: P
authors.lastname: Ghosh
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.forename: Ralph W
authors.initials: RW
authors.lastname: DeVere White
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015197:Carcinogenicity Tests; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C410798:AR protein, human; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen