Reactivation Of Androgen Receptor-regulated TMPRSS2:ERG Gene Expression In Castration-resistant Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 10 Sep 2009 - 3:00 PDT

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UroToday.com - A gene fusion between the TMPRSS2 androgen regulated gene and ERG transcription factor occurs in up to 50% of primary prostate cancers (CaP) and plays a role in the early development of CaP. In the online edition of Cancer Research, Dr. Changmeng Cai and the group of Dr. Steven Balk at Harvard University evaluate whether the TMPRSS2:ERG gene fusion is reactivated following androgen-deprivation therapy (ADT) and the development of castration-resistant prostate cancer (CRPC).

TMPRSS2 is decreased with ADT, but whether TMPRSS2:ERG is decreased is unknown. To explore this, the researchers used the VCaP cell line which expresses androgen receptor (AR) and TMPRSS2:ERG. VCaP cells initially decrease TMPRSS2:ERG in response to ADT. ERG expression was induced in VCaP cells with exposure to low dose DHT and this suppressed the AR inhibitor bicalutamide. The expression of TMPRSS2 was even two-fold higher. Knock-down of ERG using siRNA did not affect cell growth either in the presence or absence of DHT. VCaP cells were grown in mice. Tissue was examined 4 days prior to castration, 6 weeks after, and when xenograft tumors were 1 cm in size. Both TMPRSS2 and ERG as well as PSA decreased after castration and increased in the relapsed tumors. Furthermore, enzymes regulating the biosynthesis of intracrine androgens were increased in recurrent tumors.

Using clinical bone marrow metastatic samples from CRPC, TMPRSS2:ERG RNA transcripts were detected in 11 of 29 cases. This was similar to an evaluation of expression of TMPRSS2:ERG RNA transcripts in a cohort of primary prostate cancer samples. These data suggest that TMPRSS2:ERG is not only androgen regulated, but CRPC tumors expressing TMPRSS2:ERG demonstrate intracrine androgen biosynthesis and levels of gene fusion protein similar to pre-castration levels.

Cai C, Wang H, Xu Y, Chen S, Balk SP
Cancer Res. 2009 Aug 1;69(15):6027-32.
doi:10.1158/0008-5472

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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