The E3 ubiquitin ligase Cbl-b improves the prognosis of RANK positive breast cancer patients by inhibiting RANKL-induced cell migration and metastasis

Abstract

The receptor activator of nuclear factor κ-B ligand (RANKL)/RANK pathway plays an important role in breast cancer progression. Despite the known role of Casitas B-lineage lymphoma (Cbl)-b as an essential regulator of the RANKL/RANK pathway, its effect on RANK pathway in breast cancer remains unclear. Thus, the present study investigated the effect of Cbl-b on the prognosis of RANK-expressing breast cancer patients, as well as on RANKL/RANK pathway. The results showed that RANK and Cbl-b expression was separately detected in 154 (154/300, 51.3%) and 165 (165/300, 55.0%) breast cancer tissue samples. In RANK-expressing breast cancer patients, Cbl-b expression was correlated with low metastasis rate (p = 0.004), better disease-free survival (DFS) and breast cancer-specific survival (BCSS) (p = 0.004 and p = 0.036, respectively). In addition, multivariate analysis showed that Cbl-b expression was an independent predictor of DFS (p = 0.038). Animal experiment results demonstrated that silencing Cbl-b expression in breast cancer cells increased the incidence of lung metastasis in nude mice. Further mechanism investigation revealed that Cbl-b down-regulated RANK protein expression and inhibited RANKL-induced breast cancer cell migration by negatively regulating the Src-Akt/ERK pathway. Our results suggest that Cbl-b improves the prognosis of RANK-expressing breast cancer patients by inhibiting RANKL-induced breast cancer cell migration and metastasis.