Epigenetic restoration and activation of ERβ: an inspiring approach for treatment of triple-negative breast cancer

Background Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and HER2-targeted therapies ineffective. TNBC is typically treated with cytotoxic chemotherapy followed by surgery. Targeting epigenetic modifications could potentially be a new effective TNBC target therapy. The aim of this study is to examine the effects of epigenetic drugs, decitabine as DNA methyltransferase inhibitor (DNMTI) and vorinostat as histone deacetylase inhibitor (HDACI), and the ER beta agonist DPN on ER alpha and ER beta re-expressions in the MDA-MB-231 cells as a model of TNBC. Methods Using MTT assay, the IC50 of decitabine, vorinostat, and DPN on MDA-MB-231 cells were determined. The effects of all drugs alone or in combinations on MDA-MB-231 cells were evaluated. qRT-PCR was used to determine ER alpha & ER beta gene expression. Caspase-3 activity and the protein expression levels of VEGF, Cyclin D1, and IGF-1 were assessed. Results Both ER alpha and ER beta mRNA were re-expressed in different high levels in all treated groups, especially in the triple therapy group compared with control. Significantly, the triple drugs therapy showed the lowest levels of VEGF, Cyclin D1, and IGF-1 and the highest level of Caspase-3 activity, indicating a possible antitumor effect of ER beta activation through decreasing proliferation and angiogenesis and increasing apoptosis in MDA-MB-231 cells. Conclusions The antiproliferative effect of ER beta could be retained when co-expressed with Er alpha using a powerful epigenetic combination of Decitabine and vorinostat with DPN.