Abstract 2461: Targeting eIF4A3 as a multifunctional translation initiation factor for breast cancer therapy

Abstract

Abstract eIF4A3 is a unique eukaryotic translation initiation factor (eIF) with broad functions in the whole process of RNA metabolism, including mRNA splicing via exon junction complex (EJC), mRNA nuclear export, translation, and RNA surveillance through nonsense-mediated RNA decay (NMD). These post-transcriptional processes are highly involved in cancer development. However, the roles of eIF4A3 in cancers have not addressed. In this study, by analyzing a breast cancer patient database, we identified that the up-regulation of eIF4A3 is correlated with poor survival of triple negative breast cancer (TNBC) patients. Overexpression of eIF4A3, along with other EJC components (Magoh, Y14 and CASC3), were observed in multiple TNBC cell lines as compared to human normal cells and mouse normal tissues. Knockdown of eIF4A3 by RNAi was found to strongly inhibit TNBC cell proliferation in vitro; down-regulation of endogenous eIF4A3 also suppressed tumor growth in a mouse model. Dominant negative eIF4A3 and an ATP-binding defective mutants inhibited TNBC cell growth in the clonogenic assay. Furthermore, TNBC cells were found to be more sensitive to eIF4A3-specific inhibitors than luminal A and B subtypes of breast cancer cells. Thus, our study elucidates a strong cancer-promoting activity of eIF4A3 in breast cancer growth at cellular and animal model levels, warranting a new strategy to target eIF4A3 for breast cancer therapy, especially for TNBC as the most difficult subtype to treat. Citation Format: Jun Ling, Allen Huang, Ai Ohno, Joe Chen, Maria Cavataio. Targeting eIF4A3 as a multifunctional translation initiation factor for breast cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2461.