Prostate cancer is an
androgen-dependent disease; metastatic
prostate cancer is typically treated by
androgen receptor (AR) blockade. Recurrence after
androgen ablation and evidence that AR continues to play a role in many
prostate cancers has led to an examination of other factors that potentiate AR activity. AR is a
ligand-activated
transcription factor whose activity is regulated not only by
hormone but also by the levels of coactivators recruited by AR to facilitate transcription. We sought to assess the consequences of reducing expression of the
transcription intermediary factor 2 (TIF2) coactivator on
prostate cancer cell growth and AR action in cell lines to examine TIF2 expression in
prostate cancer and to correlate expression with clinical outcome. Depletion of TIF2 reduced expression of AR-induced target genes and slowed proliferation of AR-dependent and AR-independent
prostate cancer cells. Remarkably, we found that TIF2 expression is directly repressed by high levels of
androgens in multiple AR-expressing cell lines. Expression of a reporter containing 5'-flanking region of the TIF2 was repressed both by
androgens and by the antagonist,
Casodex. Expression of TIF2 correlates with biochemical (
prostate-specific antigen) recurrence (P = 0.0136). In agreement with our in vitro findings, the highest expression of TIF2 was found in patients whose
cancer relapsed after
androgen ablation
therapy, supporting the idea that AR blockade might activate pathways that lead to stimulation of AR-dependent and AR-independent proliferation of prostate epithelium. The elevated expression of TIF2 at low
hormone levels likely
aids in inducing AR activity under these conditions; treatment with
Casodex has the potential to counteract this induction.