Induction of the mesenchymal to epithelial transition by demethylation- activated microRNA-200c is involved in the anti-migration/invasion effects of arsenic trioxide on human breast cancer cells

Breast cancer is a major health problem worldwide. Current standard practices for treatment of breast cancer are less than satisfactory because of high rates of metastasis. Arsenic trioxide (As2O3), which induces demethylation of DNA and causes apoptosis, has been used as an anti-tumor agent. Little is known, however, regarding its anti-metastatic effects. The microRNA-200c (miR-200c), which is frequently lowly expressed in triple negative breast cancers (TNBCs), inhibits metastasis by inducing the mesenchymal to epithelial transition (MET). Here, we report that As2O3 attenuates the migratory and invasive capacities of breast cancer cells, MDA-MB-231 and BT-549. Notably, As2O3 induces an MET in vitro and in vivo, as determined by the increased expression of the epithelial marker, E-cadherin and decreased expressions of mesenchymal markers, N-cadherin and vimentin. Moreover, As2O3 up-regulates the expression of miR-200c through demethylation. Over-expression of miR-200c enhances the expression of E-cadherin and decreases the expressions of N-cadherin and vimentin. Further, in MDA-MB-231 cells exposed to As2O3, knockdown of miR-200c blocks the As2O3-induced MET. Finally, in MDA-MB-231 and BT-549 cells exposed to As2O3, knockdown of miR-200c decreases the As2O3-induced inhibition of the migratory and invasive capacities. By identifying a mechanism whereby As2O3 regulates miR-200c and MET, the results establish the anti-migration/invasion potential of arsenic trioxide. (c) 2014 Wiley Periodicals, Inc.