FUNCTIONS, REGULATION AND MECHANISMS OF WBP2 IN BREAST CANCER

Abstract

WW-domain binding protein 2 (WBP2) is a transcriptional co-activator that is critical for breast carcinogenesis. In this study, an integrated proteogenomic meta-analysis was performed on TCGA BRCA to define alternative roles of WBP2, and WBP2 was observed to be associated with inflammatory pathways. Experimentally, we demonstrated that WBP2 enhanced cell migration, as well as NFkB transcriptional activity and nuclear localisation in triple-negative breast cancer (TNBC) cell lines, especially under the stimulation of pro-inflammatory TNFa cytokine. In-depth mechanistic insights revealed WBP2 as a negative regulator of IkBa, an upstream inhibitor of NFkB. WBP2 expression augmented IkBa ubiquitination through enhancing the expression of BTRC E3 ubiquitin ligase. Functionally, BTRC was shown to be essential for WBP2-driven cell migration in TNBC cell lines. Collectively, our findings revealed a novel WBP2/BTRC/IkBa signaling axis that is important for TNBC biology.