Dual Suppressive Effect of miR-34a on the FOXM1/eEF2-Kinase Axis Regulates Triple-Negative Breast Cancer Growth and Invasion

Abstract

<b>Purpose:</b> Recent studies indicated that dysregulation of noncoding RNAs (ncRNA) such as miRNAs is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC).<b>Experimental Design:</b> We performed <i>in vitro</i> functional assays on TNBC cell lines to investigate the role of miR-34a in FOXM1/eEF2K signaling axis. TNBC tumor xenograft models were used for <i>in vivo</i> therapeutic delivery of miR-34a.<b>Results:</b> In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic <i>eEF2K</i>, which was associated with significantly shorter overall patient survival. We showed that miR-34a directly binds to the 3'-untranslated region of <i>eEF2K</i> and <i>FOXM1</i> mRNAs and suppresses their expression, leading to inhibition of TNBC cell proliferation, motility, and invasion. Notably, restoring miR-34a expression recapitulated the effects of inhibition of <i>eEF2K</i> and <i>FOXM1</i>, the transcription factor for <i>eEF2K</i> and the direct target of p53, in TNBC cell lines, whereas overexpression of <i>eEF2K</i> and <i>FOXM1</i> rescued the effects and signaling pathways mediated by miR-34a. Moreover, <i>in vivo</i> therapeutic delivery of miR-34a nanoparticles by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis, and inducing apoptosis.<b>Conclusions:</b> Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a-based gene therapy may be a potential therapeutic strategy in TNBC. <i>Clin Cancer Res; 24(17); 4225-41. ©2018 AACR</i>.