lincRNA-RoR and miR-145 Regulate Invasion in Triple-Negative Breast Cancer via Targeting ARF6

Abstract

Triple-negative (ER⁻, HER2⁻, PR⁻) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of microRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 downregulation in TNBC was examined. Overexpression of the long intergenic noncoding RNA regulator of reprogramming, lincRNA-RoR, functions as a competitive endogenous RNA sponge in TNBC. Interestingly, lincRNA-RoR is dramatically upregulated in TNBC and in metastatic disease and knockdown restores miR-145 expression. Previous reports suggest that miR-145 has growth-suppressive activity in some breast cancers; however, these data in TNBC indicate that miR-145 does not affect proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Investigation of miR-145-regulated pathways involved in tumor invasion revealed a novel target, the small GTPase ADP-ribosylation factor 6 (Arf6). Subsequent analysis demonstrated that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in TNBC and in breast tumor metastasis. Mechanistically, ARF6 regulates E-cadherin localization and affects cell–cell adhesion. These results reveal a lincRNA-RoR/miR-145/ARF6 pathway that regulates invasion in TNBCs. Implications: The lincRNA-RoR/miR-145/ARF6 pathway is critical to TNBC metastasis and could serve as biomarkers or therapeutic targets for improving survival. Mol Cancer Res; 13(2); 330–8. ©2014 AACR.