Abstract 1463: Long non-coding RNA RoR and microRNA-145 regulate tumor cell invasion in triple-negative breast cancer via targeting of ADP-ribosylation factor 6

Abstract

Abstract Triple-negative (ER-, HER2-, PR-) breast cancer (TNBC) is an aggressive disease with a poor prognosis. Currently, there is no available molecularly targeted therapy for TNBC. MicroRNA-145 (miR-145) silencing was identified as a defining marker of TNBC by molecular profiling using deep sequencing. Previous reports indicate that miR-145 may function as a growth suppressor in some breast cancers. However, we find that in TNBC miR-145 does not regulate proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Since metastatic breast cancer remains an incurable disease we investigated miR-145 regulated pathways to identify new potential biomarkers or therapeutic targets. Here we identify a novel target of miR-145, the small GTPase ADP-ribosylation factor 6 (Arf6). We find that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in triple-negative and metastatic breast tumors. We find that ARF6 can regulate E-cadherin localization and impact cell-cell adhesion. Finally, we examined the molecular mechanism behind miR-145 down-regulation in TNBC. We find that when compared to ER+ disease, TNBC shows dramatic downregulation of mature miR-145, but not pri-miR-145 or pre-miR-145, indicating that loss of miR-145 is occurring post-transcriptionally and following Drosha and Dicer processing. We find that overexpression of the long non-coding RNA, lincRNA-ROR, functions as a competitive endogenous RNA sponge in TNBC. We find that lincRNA-ROR is dramatically upregulated in TNBC and in metastatic disease. Finally, we find that knockdown of lincRNA-ROR restores miR-145 expression and reduces breast tumor cell invasion. These results reveal a lincRNA-ROR / miR-145 / ARF6 pathway that is a critical regulator of invasion in TNBCs. Citation Format: Gabriel L. Eades, Qun Zhou. Long non-coding RNA RoR and microRNA-145 regulate tumor cell invasion in triple-negative breast cancer via targeting of ADP-ribosylation factor 6. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1463. doi:10.1158/1538-7445.AM2014-1463