The oncogenic potential of a prostate cancer-derived androgen receptor mutant.
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.
Shi
Xu-Bao
XB
Department of Urology, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
Xue
Lingru
L
Tepper
Clifford G
CG
Gandour-Edwards
Regina
R
Ghosh
Paramita
P
Kung
Hsing-Jien
HJ
DeVere White
Ralph W
RW
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
C410798:AR protein, human; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen