Differential expression of androgen receptor variants in hormone-sensitive prostate cancer xenografts, castration-resistant sublines, and patient specimens according to the treatment sequence.

Abstract

Androgen receptor variants (AR-vs), especially AR-v7 and AR-v 5, 6, and 7 exon-skipped (AR-v567es), are reportedly key players in the development of castration-resistant prostate cancer (CRPC). We previously established a mouse xenograft model (JDCaP) from a metastatic skin lesion from a Japanese patient with CRPC and that was revealed to exhibit androgen sensitivity. In the present study, we established multiple castration-resistant xenograft models from JDCaP mice to investigate the biological features of CRPC. Tissue from JDCaP mice was transplanted into male and female nude mice, and after serial passaging, castration-resistant sublines (JDCaP-CR2M and JDCaP-CR4M in male mice, JDCaP-CR2F and JDCaP-CR4F in female mice) were established. We investigated anti-androgen and testosterone sensitivity and the messenger RNA expression pattern of full-length AR and AR-vs. In addition, we compared AR protein levels of patient specimens among primary, local-recurrent, and two skin-metastatic tumors. All JDCaP-CR sublines showed continuous growth following the administration of bicalutamide, although the effects of testosterone varied among sublines. Parental JDCaP and JDCaP-CR2M, JDCaP-CR4M, and JDCaP-CR4F sublines expressed AR-v7, whereas JDCaP-CR2F exhibited elevated AR-v567es expression resulting from genomic deletion, which was confirmed by DNA sequencing. Moreover, we confirmed AR-v7 expression in the tumor of the original patient after androgen-deprivation therapy. Each JDCaP-CR subline showed different AR-v-expression patterns, with JDCaP-CR2F expressing AR-v567es due to genomic deletion. Our results indicated that AR-vs emerged after androgen-deprivation therapy and appeared essential for acquisition of castration resistance.