In conclusion, by using a panel of breast cancer cell lines, we provided compelling evidence that carfilzomib alone could suppress the proliferation and induce apoptosis in breast cancer cells and enhance the cytotoxic effect of DOX and DOX-induced apoptosis in combination by preventing IκBα degradation in the NF-κB signal pathway and activating JNK apoptotic signaling. Here, NFKB1 is linked to breast cancer.