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.
Highlights
Breast cancer is the most common cancer in women worldwide, and the occurrence of metastatic disease increases mortality and affects quality of life
Preclinical observations suggest that RANKL promotes bone and lung metastasis via the direct pro-metastatic effects of RANKL on RANK expressing breast cancer cells [9] independently of osteoclasts, implying that the RANKL/RANK pathway may play a role in non-bone metastasis
RANK was expressed in 51.3% of breast cancer tissues, and RANK expression was not associated with poor prognosis, which was an unpredictable result
Summary
Breast cancer is the most common cancer in women worldwide, and the occurrence of metastatic disease increases mortality and affects quality of life. In a different study, RANK mRNA expression was not associated with poor prognosis in breast cancer patients [13] Another www.impactjournals.com/oncotarget study even reported that high levels of RANK or RANKL mRNA expression were correlated with better overall survival [14]. Our previous study demonstrated that the UPS inhibitor bortezomib upregulates RANK expression and enhances RANKL-induced breast cancer cell migration [22], suggesting that the UPS is a negative regulator of the RANK pathway. The effect of Cbl-b on RANKL induced breast cancer cell migration is unclear, and whether it plays a role in the prognosis of RANK-expressing breast cancer patients remains to be elucidated. Cbl-b suppressed RANK expression and inhibited RANKLinduced breast cancer cell migration and metastasis through the negative regulation of the Src/Akt and Src/ ERK pathways. Our results provide new insight into the regulatory mechanism of RANKL/RANK pathwaymediated breast cancer cell migration, and suggest that combined analysis of Cbl-b and RANK as biomarkers could be useful for the characterization of breast cancer patients
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