NRBE3 promotes metastasis of breast cancer by down-regulating E-cadherin expression.

NRBE3 acts as an E3 ligase of RB to promote RB's polyubiquitination and degradation. In addition, NRBE3 is up-regulated in human breast cancer (BC) tissues. However, how NRBE3 functions in BC is unknown. Here, we show that up-regulation of NRBE3 is correlated with lymphatic metastasis in human BC tissues. Ectopic expression of NRBE3 promotes migration and invasion in BC cells. Accordingly, knockdown of NRBE3 inhibits migration and invasion in BC cells. Depletion of NRBE3 inhibits lung metastasis of BC cells in vivo. Knock-down of NRBE3 causes increase of E-cadherin protein levels. Interestingly, Flag-NRBE3 decreases E-cadherin level in RB-expressing and RB-null BC cells, demonstrating that there exist RB-independent mechanisms for NRBE3-mediated E-cadherin expression regulation. However, the E3 ligase deficient deletion mutant Flag-NRBE3 (ΔU-box) modestly decreases E-cadherin level in RB-expressing cells, indicating that NRBE3 controls E-cadherin expression mainly through RB-dependent pathways in RB-expressing cells. We further demonstrate that NRBE3 inhibits the transcription of E-cadherin in BC cells. Significantly, NRBE3 expression is negatively correlated with E-cadherin expression in human BC tissues and cell lines. Collectively, we demonstrate that NRBE3 promotes metastasis of BC and possesses the potential as a therapeutic target in BC.