Androgen receptor modifications in prostate cancer cells upon long-termandrogen ablation and antiandrogen treatment.
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| Abstract |
To study the mechanisms whereby androgen-dependent tumors relapse in patients undergoing androgen blockade, we developed a novel progression model for prostate cancer. The PC346C cell line, established from a transurethral resection of a primary tumor, expresses wild-type (wt) androgen receptor (AR) and secretes prostate-specific antigen (PSA). Optimal proliferation of PC346C requires androgens and is inhibited by the antiandrogen hydroxyflutamide. Orthotopic injection in the dorsal-lateral prostate of castrated athymic nude mice did not produce tumors, whereas fast tumor growth occurred in sham-operated males. Three androgen-independent sublines were derived from PC346C upon long-term in vitro androgen deprivation: PC346DCC, PC346Flu1 and PC346Flu2. PC346DCC exhibited androgen-insensitive growth, which was not inhibited by flutamide. AR and PSA were detected at very low levels, coinciding with background AR activity in a reporter assay, which suggests that these cells have bypassed the AR pathway. PC346Flu1 and PC346Flu2 were derived by culture in steroid-stripped medium supplemented with hydroxyflutamide. PC346Flu1 strongly upregulated AR expression and showed 10-fold higher AR activation than the parental PC346C. PC346Flu1 proliferation was inhibited in vitro by R1881 at 0.1 nM concentration, consistent with a slower tumor growth rate in intact males than in castrated mice. PC346Flu2 carries the well-known T877A AR mutation, causing the receptor to become activated by diverse nonandrogenic ligands including hydroxyflutamide. Array-based comparative genomic hybridization revealed little change between the various PC346 lines. The common alterations include gain of chromosomes 1, 7 and 8q and loss of 13q, which are frequently found in prostate cancer. In conclusion, by in vitro hormone manipulations of a unique androgen-dependent cell line expressing wtAR, we successfully reproduced common AR modifications observed in hormone-refractory prostate cancer: downregulation, overexpression and mutation.
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| Authors | Rute B Marques, Sigrun Erkens-Schulze, Corrina M de Ridder, Karin G Hermans, Kati Waltering, Tapio Visakorpi, Jan Trapman, Johannes C Romijn, Wytske M van Weerden, Guido Jenster |
| Journal | International journal of cancer (Int J Cancer) Vol. 117 Issue 2 Pg. 221-9 (Nov 01 2005) ISSN: 0020-7136 [Print] United States |
| PMID | 15900601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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