Vitamin C counteracts miR‐302/367‐induced reprogramming of human breast cancer cells and restores their invasive and proliferative capacity

Abstract Epigenetic reprogramming by embryonic stem cell‐specific miR‐302/367 cluster has shown some tumor suppressive effects in cancer cells of different tissues such as skin, colon, and cervix. Vitamin C has been known as a reprogramming enhancer of human and mouse somatic cells. In this study, first we aimed to investigate whether exogenous induction of miR‐302/367 in breast cancer cells shows the same tumor suppressive effects previously observed in other cancer cells lines, and whether vitamin C can enhance reprogramming of breast cancer cells and also improve the tumor suppressive function of miR‐302/367 cluster. Overexpression of miR‐302/367 cluster in MDA‐MB‐231 and SK‐BR‐3 breast cancer cells upregulated expression of miR‐302/367 members and also some core pluripotency factors including OCT4A , SOX2 and NANOG , induced mesenchymal to epithelial transition, suppressed invasion, proliferation, and induced apoptosis in the both cell lines. However, treatment of the miR‐302/367 transfected cells with vitamin C suppressed the expression of pluripotency factors and augmented the tumorigenicity of the breast cancer cells by restoring their proliferative and invasive capacity and compromising the apoptotic effect of miR‐302/367. Supplementing the culture medium with vitamin C downregulated expression of TET1 gene which seems to be the reason behind the negative impact of vitamin C on the reprogramming efficiency of miR‐302/367 cluster and its anti‐tumor effects. Therefore application of vitamin C may not always serve as a reprogramming enhancer depending on its switching function on TET1 . This phenomenon should be carefully considered when considering a reprogramming strategy for tumor suppression.