Abstract 1847: AR-V7 regulation during epithelial plasticity

Abstract

Abstract Background: The androgen receptor (AR) is a key gene involved in prostate cancer (PC) biology, including disease development, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. AR variants lacking the ligand-binding domain, such as AR-V7, have been observed and enriched in metastatic castration resistant prostate cancer. These variants contribute to resistance mechanisms against agents that target hormonal regulation of the AR, including anti-androgens, such as enzalutamide. In addition to AR variants, epithelial plasticity, including an epithelial-to-mesenchymal transition (EMT), has been implicated in PC metastatic dissemination during castration-resistance. In response to androgen deprivation therapy, PC xenografts have been found to display an acute and reversible up-regulation of both EMT phenotypic markers and AR variants. Methods: To explore the mechanism by which an EMT program may regulate AR variant expression and metastatic disease, we used pre- and post- EMT cells to compare AR expression, migration, invasion and enzalutamide resistance. To induce EMT, we stably transfected LNCaP95 PC cells with a plasmid encoding inducible Snail, a master regulator of EMT. In addition, LNCAP95 cells were serially passaged under increasing enzalutamide conditions and we assessed biomarkers of EMT and invasion/growth in resistant cells. Results: We found that Snail activation was sufficient to induce an EMT and increased expression of both AR-FL and AR-V7 as compared to pre-EMT cells. Nuclear localization of AR, migration and invasion were also increased in post-EMT cells. Importantly, cells were more resistant to enzalutamide treatment. Likewise, in a second model of acquired enzalutamide resistance, we found that Snail, AR-FL and AR-V7 were upregulated in enzalutamide resistant vs. sensitive cell lines. Conclusion: Our study suggests that Snail activation promotes both an aggressive and therapy resistant tumor cell through the induction of EP and both AR-FL and AR-V7 isoforms. Citation Format: Kathryn E. Ware, Daneen Schaeffer, Tian Zhang, Mariano A. Garcia-Blanco, Andrew J. Armstrong. AR-V7 regulation during epithelial plasticity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1847. doi:10.1158/1538-7445.AM2015-1847