Abstract 1988: MYB overexpression is associated with castration-resistance in prostate cancer

Abstract

Abstract Clinical progression of prostate cancer (PCa) is characterized by a transition from castration-sensitive (CS) to castration-resistant (CR) phenotype. We previously demonstrated that MYB overexpression sustained the growth of PCa cells in androgen-depleted growth environment as well as promoted aggressive tumor phenotypes. Here, we examined its role in PCa progression and castration-resistance using appropriate mouse models and delineated underlying molecular mechanisms. Luciferase-tagged MYB-overexpressing (LNCaP-MYB) or -silenced (C4-2-shMYB) PCa cell lines along with their respective control sublines (LNCaP-Neo and C4-2-NTScr) were orthotopically implanted in nude mice and tumor growth was monitored by non-invasive bioluminescence imaging using Xenogen-IVIS optical system. Our data demonstrated significantly enhanced tumor growth in mice implanted with high MYB expressing (LNCaP-MYB and C4-2-NTScr) PCa cells as compared to low MYB expressing (LNCaP-Neo and C4-2-shMYB) cells. To study the role of MYB in castration-resistance, we castrated the mice after tumors from all groups reached comparable size as determined by in vivo imaging. Tumors in LNCaP-Neo and C4-2-shMYB groups exhibited drastic regression following castration. In contrast, only slight initial reduction in the tumor growth was reported in mice from LNCaP-MYB and C4-2-NTScr groups following castration, and they later regained tumor growth. Furthermore, Kaplan-Meier survival analysis revealed that the median survival of testis-intact (non-castrated) animals of LNCaP-Neo and C4-2-shMYB groups was significantly lower than that of castrated group mice. However, castration in high MYB-expressing tumor bearing mice could barely improve their median survival. Interestingly, MYB expression levels in orthotopic tumors correlated with serum PSA levels. Furthermore, castration of mice in LNCaP-Neo and C4-2-shMYB groups resulted in a rapid reduction in serum PSA levels; while it sustained and continued to rise in MYB overexpressing groups. In additional studies, we demonstrated that MYB interacts with androgen-receptor (AR) in prostate cancer cells, and facilitates the nuclear localization of AR in a ligand-independent manner. In essence, these results suggest a critical role of MYB in the CR progression of PCa. Citation Format: Sanjeev K. Srivastava, Arun Bhardwaj, Seema Singh, Sumit Arora, Nikhil Tyagi, James E. Carter, Ajay P. Singh. MYB overexpression is associated with castration-resistance in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1988.