Our results demonstrated in vitro that concurrent exposure of equipotent doses of an HDACi (e.g., VPA, vorinostat, panobinostat and entinostat) and 5′-DFUR, resulted in synergistic/additive antiproliferative and pro-apoptotic effects in all breast cancer cell lines examined and that these effects were independent of their characteristics and genetic backgrounds, being observed in ER+ MCF-7, HER-2 overexpressing SKBR3 or triple-negative MDA-468 cells. The gene discussed is ESR1; the disease is breast cancer.