WW-domain-binding protein 2 (WBP2) is an oncogene that drives breast carcinogenesis through regulating Wnt, estrogen receptor (ER), and Hippo signaling. Recent studies have identified neoteric modes of action of WBP2 other than its widely recognized function as a transcriptional coactivator. Here, we identified a previously unexplored role of WBP2 in inflammatory signaling in breast cancer via an integrated proteogenomic analysis of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA BRCA) dataset. WBP2 was shown to enhance the migration and invasion in triple-negative breast cancer (TNBC) cells especially under tumor necrosis factor alpha (TNF-α) stimulation. Molecularly, WBP2 potentiates TNF-α-induced nuclear factor kappa B (NF-κB) transcriptional activity and nuclear localization through aggrandizing ubiquitin-mediated proteasomal degradation of its upstream inhibitor, NF-κB inhibitor alpha (NFKBIA; also known as IκBα). We further demonstrate that WBP2 induces mRNA stability of beta-transducin repeat-containing E3 ubiquitin protein ligase (BTRC), which targets IκBα for ubiquitination and degradation. Disruption of IκBα rescued the impaired migratory and invasive phenotypes in WBP2-silenced cells, while loss of BTRC ameliorated WBP2-driven migration and invasion. Clinically, the WBP2-BTRC-IκBα signaling axis correlates with poorer prognosis in breast cancer patients. Our findings reveal a pivotal mechanism of WBP2 in modulating BTRC-IκBα-NF-κB pathway to promote TNBC aggressiveness.