Reactivation of androgen receptor-regulated TMPRSS2:ERG gene expression in castration-resistant prostate cancer.

ABSTRACT

It seems clear that androgen receptor (AR)-regulated expression of the TMPRSS2ERG fusion gene plays an early role in prostate cancer (PC) development or progression, but the extent to which TMPRSS2ERG is down-regulated in response to androgen deprivation therapy (ADT) and whether AR reactivates TMPRSS2ERG expression in castration-resistant PC (CRPC) have not been determined. We show that ERG message levels in TMPRSS2ERG fusion-positive CRPC are comparable with the levels in fusion gene-positive primary PC, consistent with the conclusion that the TMPRSS2ERG expression is reactivated by AR in CRPC. To further assess whether TMPRSS2ERG expression is initially down-regulated in response to ADT, we examined VCaP cells, which express the TMPRSS2ERG fusion gene, and xenografts. ERG message and protein rapidly declined in response to removal of androgen in vitro and castration in vivo. Moreover, as observed in the clinical samples, ERG expression was fully restored in the VCaP xenografts that relapsed after castration, coincident with AR reactivation. AR reactivation in the relapsed xenografts was also associated with marked increases in mRNA encoding AR and androgen synthetic enzymes. These results show that expression of TMPRSS2ERG, similarly to other AR-regulated genes, is restored in CRPC and may contribute to tumor progression.