Inhibition of miR-10b treats metastatic breast cancer by targeting stem cell-like properties. Inhibition of miR-10b treats metastatic breast cancer by targeting stem cell-like properties

Despite advances in breast cancer screening and treatment, prognosis for metastatic disease remains dismal at 30% five-year survival. This is due, in large, to the failure of current therapeutics to target properties unique to metastatic cells. One of the drivers of metastasis is miR-10b, a small noncoding RNA implicated in cancer cell invasion, migration, viability, and proliferation. We have developed a nanodrug termed MN-anti-miR10b that delivers anti-miR10b antisense oligomers to cancer cells. In mouse models of metastatic triple-negative breast cancer, MN-anti-miR10b has been shown to prevent onset of metastasis and eliminate existing metastasis in combination with chemotherapy even after treatment has been stopped. Recent studies have implicated miR-10b in conferring stem cell-like properties onto cancer cells, such as chemoresistance. In this study, we show transcriptional evidence that inhibition of miR-10b with MN-anti-miR10b activates developmental processes in cancer cells and that stem-like cancer cells have increased miR-10b expression. We then demonstrate that treatment of breast cancer cells with MN-anti-miR10b reduces their stemness confirming that these properties make metastatic cells susceptible to the nanodrug actions. Collectively, these findings indicate that inhibition of miR-10b functions to impair breast cancer cell stemness, positioning MN-anti-miR10b as an effective treatment option for stem-like breast cancer subtypes. Overall design: To identify therapeutic mechanisms of mir-10b inhibition, MDA-MB-231 and 4T1 breast cancer cells were treated with MN-anti-miR10b (anti-miR-10b nanodrug), magnetic nanoparticle (MN; vehicle), or left them untreated for 48 hours. We then performed differential gene expression analysis of data from RNA-seq analysis and functional enrichment analyses on significantly upregulated and downregulated genes.