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The oncogenic potential of a prostate cancer‐derived androgen receptor mutant
Author(s) -
Shi XuBao,
Xue Lingru,
Tepper Clifford G.,
GandourEdwards Regina,
Ghosh Paramita,
Kung HsingJien,
deVere White Ralph W.
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20544
Subject(s) - androgen receptor , transfection , prostate cancer , cancer research , lncap , prostate , downregulation and upregulation , biology , carcinogenesis , cell culture , nude mouse , microbiology and biotechnology , cancer , gene , genetics
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. CONCLUSION 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. Prostate 67: 591–602, 2007. © 2007 Wiley‐Liss, Inc.