The oncogenic potential of a prostate cancer-derived androgen receptor mutant

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17 Scopus citations

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 (ARK580R) 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 ARWT, the ARK580R induced greater than sixfold increase in colony formation in soft agar. In vivo studies confirmed that the ARK580R-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 ARK580R cells. It was found that silencing the expression of placental alkaline phosphatase (ALPP) that was upregulated in ARK580R cells resulted in significant inhibition of cell growth. Furthermore, the ARK580R-transfected pRNS-1-1 cells expressed markedly increased p-Akt and p-p70 S6K. CONCLUSION. The ARK580R mutation promoted the malignant transformation of prostate epithelial cells. This was associated with upregulation of ALPP and subsequent activation of the Akt signaling pathway.

Original languageEnglish (US)
Pages (from-to)591-602
Number of pages12
JournalProstate
Volume67
Issue number6
DOIs
StatePublished - May 1 2007

Keywords

  • Androgen receptor mutation
  • Prostate cancer
  • Tumorigenesis

ASJC Scopus subject areas

  • Urology

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