Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes

The human prostate cancer (CaP) xenograft, CWR22, mimics human Cap, CWR22 g rows in testosterone-stimulated nude mice, regresses after castration, and recurs after 5-6 months in the absence of testicular androgen. Like human C ap that recurs during androgen deprivation therapy, the recurrent CWR22 exp resses 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 CW R22 prior to castration. Expression of prostate-specific antigen and human kallikrein-2 mRNAs, two well-characterized androgen-regulated genes in huma n Cap, was androgen dependent in CWR22. Despite the absence of testicular a ndrogen, prostate-specific antigen and human kallikrein-2 mRNA levels in re current CWR22 were higher than the levels in regressing CWR22 tumors from 1 2-day castrate mice and similar to those in the androgen-stimulated CWR22. Other AR-regulated genes followed a similar pattern of expression. Differen tial expression screening identified androgen regulation of alpha-enolase a nd alpha-tubulin as well as other unknown mRNAs, Insulin-like growth factor binding protein-5, the homeobox gent Nkx 3.1, the AR coactivator ARA-70, a nd cell cycle genes Cdk1 and Cdk2 were androgen regulated in CWR22, In recu rrent CWR22, the steady-state levels of all these AR-dependent mRNAs were s imilar to those in the androgen-stimulated CWR22, despite the absence of te sticular 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 ne twork might result from a non-AR transcription control mechanism common to these genes.