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Abstract
Abstract Expression of androgen receptor (AR) variants (AR-Vs) lacking the AR ligand binding domain (LBD) in prostate cancer tissues or circulating tumor cells is associated with poor clinical outcomes. AR-Vs function as constitutively active transcription factors and represent a resistance mechanism whereby the growth of prostate cancer cells can remain AR-dependent, yet uncoupled from endocrine regulation. Tumors that have developed this mechanism of resistance are unlikely to respond to successive generations of endocrine therapies. The absence of a LBD presents a formidable challenge for direct inhibition of AR-Vs because alternative sites on the AR protein appropriate for specific and high-affinity drug targeting are not evident. An indirect approach may be through inhibition of AR-V expression and/or transcriptional activation mechanisms. To this end, we have found that treatment of prostate cancer cell lines with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR and AR-V chromatin binding and impaired AR and AR-V driven prostate cancer cell growth in vitro and in vivo. These anti-AR activities were associated with JQ1-mediated reduction in binding of the BET family member BRD2 to a region near the AR transcription start-site featuring broad enrichment of histone H3 acetylated at lysine 27. Consistent with these chromatin effects at the AR locus, JQ1 treatment down-regulated AR and AR-V transcript and protein expression. Overall, these findings highlight regulation of AR and AR-V expression by BRD2, and provide pre-clinical rationale for BET inhibition as a strategy for overcoming resistance mediated by constitutively active AR-Vs in prostate cancer. Citation Format: Scott M. Dehm. Regulation of AR variants by BET bromodomains in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN06-02.
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