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Breast cancer (BC) is the second most fatal disease and is the prime cause of cancer allied female deaths. BC is caused by aberrant tumor suppressor genes and oncogenes regulated by transcription factors (TFs) like NF-κB. NF-κB is a pro-inflammatory TF that crucially alters the expressions of various genes associated with inflammation, cell progression, metastasis, and apoptosis and modulates a network of genes that underlie tumorigenesis. Herein, we focus on NF-κB signaling pathways, its regulators, and the rationale for targeting NF-κB. This review also includes TFs that maintain NF-κB crosstalk and their roles in promoting angiogenesis and metastasis. In addition, we discuss the importance of combination therapies, resistance to treatment, and potential novel therapeutic strategies including nanomedicine that targets NF-κB.