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Dominant-Negative Androgen Receptor Inhibition of Intracrine Androgen-Dependent Growth of Castration-Recurrent Prostate Cancer
Published: Tuesday, January 17, 2012
Author: Mark A. Titus et al.

by Mark A. Titus, Brian Zeithaml, Boris Kantor, Xiangping Li, Karin Haack, Dominic T. Moore, Elizabeth M. Wilson, James L. Mohler, Tal Kafri

Background

Prostate cancer (CaP) is the second leading cause of cancer death in American men. Androgen deprivation therapy is initially effective in CaP treatment, but CaP recurs despite castrate levels of circulating androgen. Continued expression of the androgen receptor (AR) and its ligands has been linked to castration-recurrent CaP growth.

Principal Finding

In this report, the ligand-dependent dominant-negative AR?142–337 (AR?TR) was expressed in castration-recurrent CWR-R1 cell and tumor models to elucidate the role of AR signaling. Expression of AR?TR decreased CWR-R1 tumor growth in the presence and absence of exogenous testosterone (T) and improved survival in the presence of exogenous T. There was evidence for negative selection of AR?TR transgene in T-treated mice. Mass spectrometry revealed castration-recurrent CaP dihydrotestosterone (DHT) levels sufficient to activate AR and AR?TR. In the absence of exogenous testosterone, CWR-R1-AR?TR and control cells exhibited altered androgen profiles that implicated epithelial CaP cells as a source of intratumoral AR ligands.

Conclusion

The study provides in vivo evidence that activation of AR signaling by intratumoral AR ligands is required for castration-recurrent CaP growth and that epithelial CaP cells produce sufficient active androgens for CaP recurrence during androgen deprivation therapy. Targeting intracrine T and DHT synthesis should provide a mechanism to inhibit AR and growth of castration-recurrent CaP.

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