The human
prostate cancer (CaP) xenograft, CWR22, mimics
human CaP. CWR22 grows in
testosterone-stimulated nude mice, regresses after
castration, and recurs after 5-6 months in the absence of testicular
androgen. Like
human CaP that recurs during
androgen deprivation
therapy, the recurrent CWR22 expresses high levels of
androgen receptor (AR). Immunohistochemical, Western, and Northern blot analyses demonstrated that AR expression in the
androgen-independent CWR22 is similar to AR expression in the
androgen-dependent CWR22 prior to
castration. Expression of
prostate-specific antigen and human kallikrein-2 mRNAs, two well-characterized
androgen-regulated genes in
human CaP, was
androgen dependent in CWR22. Despite the absence of testicular
androgen,
prostate-specific antigen and human kallikrein-2
mRNA levels in recurrent CWR22 were higher than the levels in regressing CWR22
tumors from 12-day castrate mice and similar to those in the
androgen-stimulated CWR22. Other AR-regulated genes followed a similar pattern of expression. Differential expression screening identified
androgen regulation of
alpha-enolase and
alpha-tubulin as well as other unknown mRNAs.
Insulin-like growth factor binding protein-5, the homeobox gene Nkx 3.1, the AR coactivator ARA-70, and cell cycle genes Cdk1 and Cdk2 were
androgen regulated in CWR22. In recurrent CWR22, the steady-state levels of all these AR-dependent mRNAs were similar to those in the
androgen-stimulated CWR22, despite the absence of testicular
androgen. Expression of AR and AR-regulated genes in the
androgen-deprived recurrent CWR22 at levels similar to the
androgen-stimulated CWR22 suggests that AR is transcriptionally active in recurrent CWR22. Induction of these AR-regulated genes may enhance cellular proliferation in relative
androgen absence but through an AR-dependent mechanism. Alternatively, in
androgen-independent
tumors, induced expression of the AR-regulated gene network might result from a non-AR transcription control mechanism common to these genes.