NF-κB signaling in therapy resistance of breast cancer: Mechanisms, approaches, and challenges

Breast cancer is the most common type of cancer and is the second leading cause of cancer-related mortality in women. Chemotherapy, targeted therapy, endocrine therapy, and radiotherapy are all effective in destroying tumor cells, but they also activate the defense and protection systems of cancer cells, leading to treatment resistance. Breast cancer is characterized by a highly inflammatory tumor microenvironment. The NF-κB pathway is essential for connecting inflammation and cancer, as well as for tumor growth and therapy resistance. An increase in NF-κB signaling boosts the growth potential of breast cancer cells and facilitates the spread of tumors to bone, lymph nodes, lungs, and liver. This review focuses on the mechanisms by which chemotherapy, targeted therapy, endocrine therapy, and radiotherapy induce breast cancer resistance through NF-κB signaling. Additionally, we investigate therapeutic regimens, including single agents or in combination with target inhibitors, plant extracts, nanomedicines, and miRNAs, that have been reported in clinical trials, in vivo, and in vitro to reverse resistance. In particular, NF-κB inhibitors combined with tamoxifen were shown to significantly increase the sensitivity of breast cancer cells to tamoxifen. Combination therapy of miRNA-34a with doxorubicin was also found to synergistically inhibit the progression of doxorubicin-resistant breast cancer by inhibiting Notch/NF-κB signaling.