Lc. Amler et al., Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R, CANCER RES, 60(21), 2000, pp. 6134-6141
Treatment of metastatic prostate cancer with androgen-ablation often elicit
s dramatic tumor regressions, but the response is rarely complete, making c
linical recurrence inevitable with time, To gain insight into therapy-relat
ed progression, changes in gene expression that occurred following androgen
-deprivation of an androgen-dependent prostate tumor xenograft, CWR22, and
the emergence of an androgen-independent tumor, CWR22-R, were monitored usi
ng microarray analysis. Androgen-deprivation resulted in growth arrest of C
WR22 cells, as evidenced by decreased expression of genes encoding cell cyc
le components and basal cell metabolism, respiration and transcription, and
the induced expression of putative negative regulatory genes that may act
to sustain cells in a nonproliferative state. Evolution of androgen-indepen
dent growth and proliferation, represented by CWR22-R, was associated with
a reentry into active cell cycle and the up-regulation of several genes tha
t were expressed at low levels or absent in the androgen-dependent tumor. A
ndrogen repletion to mice bearing androgen-independent CWR22-R tumors induc
ed, augmented, or repressed the expression of a number of genes. Expression
of two of these genes, the calcium-binding protein S100P and the FK-506-bi
nding protein FKBP51, was decreased following androgen-deprivation, subsequ
ently reexpressed in CWR22-Rat levels comparable with CWR22, and elevated f
urther upon treatment with androgens. The dysregulated behavior of these ge
nes is analogous to other androgen-dependent genes, e.g prostate-specific a
ntigen and human kallikrein 2, which are commonly reexpressed in androgen-i
ndependent disease in the absence of androgens. Other androgen-responsive g
enes whose expression decreased during androgen-deprivation and whose expre
ssion remained decreased in CWR22 were also identified in CWR22-R, These re
sults imply that evolution to androgen-independence is due, in part, to rea
ctivation of the androgen-response pathway in the absence of androgens, but
that this reactivation is probably incomplete.