Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant.

The Journal of Clinical Investigation
Shihua SunStephen R Plymate

Abstract

Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively...Continue Reading

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Datasets Mentioned

BETA
GU208210

Methods Mentioned

BETA
xenografts
xenograft
laser-capture
biopsies
contraception
nuclear translocation
biopsy
pull
electrophoresis
PCR

Clinical Trials Mentioned

NCT00161486

Software Mentioned

EASE
Agilent Feature Extraction
Cyteseer
Statistical Analysis of Microarray ( SAM )
SAM
Excel

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