Here, we showed that the promotion of cross-resistance of breast tumor cells to hormonal and targeted drugs is underpinned by a switch of cell signaling to unblocked AKT pathways associated with a focal suppression of the NR6A1/DNMT3A axis and the corresponding alterations in DNA methylation, and illustrated the significance of NR6A1 decrease in the development of cell resistance. The gene discussed is NR6A1; the disease is breast neoplasm.