Abstract 685: Selective inhibitor of nuclear export (SINE) compounds prevent migration and proliferation of triple negative breast cancer (TNBC) cells by restoring expression of ARRDC3

Abstract

Abstract Arrestin-related domain-containing protein-3 (ARRDC3) is one of 6 mammalian arrestins, which has been shown to possess tumor suppressor activity by inducing degradation of phosphorylated â2-adrenergic receptor (â2 AR) and integrin â4 (ITG â4). Our previous studies demonstrated that Sirt2 epigenetically silenced expression of ARRDC3 in TNBC cells and overexpression of ARRDC3 significantly reduced their invasive potential. Therefore, we hypothesized that compounds, which restore ARRDC3 expression levels could serve as novel therapeutic options for TNBC. To test this, we examined the ability of SINE compounds: KPT-185 and KPT-330 (selinexor), to effectively restore ARRDC3 expression. We observed that KPT-185 and selinexor significantly induced ARRDC3 expression and inhibited the proliferation and the invasiveness of the TNBC cell lines MDA-MB-231 and MDA-MB-468 in vitro. In vivo, selinexor inhibited the tumor growth of MDA-MB-231 and MDA-MB-468 xenografts by nearly 100% compared with vehicle treated animals. Furthermore, immunohistochemical analysis of TNBC tumors from selinexor treated mice revealed increased ARRDC3 expression versus vehicle treated animals. Our results suggest that restoration of ARRDC3 expression is an important antineoplastic mechanism of SINE compounds in TNBC and suggest that selinexor could be an effective treatment against tumors with downregulated ARRDC3. Citation Format: Young Hwa Soung, Trinayan Kashyap, Thalia Nguyen, Yosef Landesman, Jun Chung. Selective inhibitor of nuclear export (SINE) compounds prevent migration and proliferation of triple negative breast cancer (TNBC) cells by restoring expression of ARRDC3. [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 685.