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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Mariko Honda, Takahiro Kimura, Yuko Kamata, Kojiro Tashiro, Shoji Kimura, Yusuke Koike, Shun Sato, Takashi Yorozu, Bungo Furusato, Hiroyuki Takahashi, Hiroshi Kiyota, Shin Egawa
• Journal: The Prostate (Prostate) Vol. 79 Issue 9 Pg. 1043-1052 (06 2019) ISSN: 1097-0045 [Electronic] United States
• PMID: 30998834 (Publication Type: Journal Article)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• AR protein, human
• Androgen Antagonists
• Anilides
• Antineoplastic Agents
• Nitriles
• RNA, Messenger
• Receptors, Androgen
• Tosyl Compounds
• Testosterone
• bicalutamide

Topics

• Androgen Antagonists (pharmacology)
• Anilides (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Female
• Gene Expression Profiling
• Heterografts
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Nitriles (pharmacology)
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptors, Androgen (biosynthesis, genetics)
• Testosterone (pharmacology)
• Tosyl Compounds (pharmacology)