Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line

Clifford G. Tepper, David L. Boucher, Philip E. Ryan, Ai Hong Ma, Liang Xia, Li Fen Lee, Thomas G. Pretlow, Hsing Jien Kung

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231 引文 斯高帕斯(Scopus)

摘要

CWR22 has been a valuable xenograft model for the study of prostate cancer progression from an androgen-dependent tumor to one that grows in castrated animals. Herein, we report the identification and characterization of a novel androgen receptor (AR) mutation occurring in a relapsed tumor (CWR22R-2152) and in the CWR22Rv1 cell line established from it. The mutation was not detected in the original, hormone-dependent CWR22 xenograft, indicating that this change occurred during the progression to androgen independence. It is characterized by an in-frame tandem duplication of exon 3 that encodes the second zinc finger of the AR DNA-binding domain. Accordingly, immunoblot analyses demonstrated the expression of an AR species having an approximately 5-kDa increase in size relative to the LNCaP AR. This was accompanied by a COOH-terminally truncated AR species migrating with a relative mass of 75-80 kDa, referred to as ARΔLBD because it lacks the ligand-binding domain. By recreating the exon 3 duplication mutation in a wild-type AR expression construct, the generation of ARΔLBD could be recapitulated. Whereas ARΔLBD exhibited constitutive nuclear localization and DNA binding, these functions in the full-length AR remained androgen dependent. The CWR22Rv1 AR repertoire displayed dose-dependent, androgen-responsive transcriptional transactivation in reporter assays, albeit to a lesser extent in comparison with LNCaP. This cell line also expressed low levels of prostate-specific antigen mRNA and did not express or secrete detectable levels of prostate-specific antigen protein in androgen-depleted medium or in response to physiological androgenic stimulation. In summary, the CWR22Rv1 cell line displays both androgen-responsive and androgen-insensitive features due, at least in part, to a novel insertional mutation of the AR.
原文英語
頁(從 - 到)6606-6614
頁數9
期刊Cancer Research
62
發行號22
出版狀態已發佈 - 11月 15 2002
對外發佈

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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