Research Papers:

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

Lingyun Zhang, Yuee Teng, Yibo Fan, Yan Wang, Wei Li, Jing Shi, Yanju Ma, Ce Li, Xiaonan Shi, Xiujuan Qu and Yunpeng Liu _

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Oncotarget. 2015; 6:22918-22933. https://doi.org/10.18632/oncotarget.4382

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Lingyun Zhang1, Yuee Teng1, Yibo Fan1, Yan Wang1, Wei Li1, Jing Shi1, Yanju Ma1, Ce Li1, Xiaonan Shi1, Xiujuan Qu1,* and Yunpeng Liu1,*

1 Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China

* These authors have contributed equally to this work

Correspondence to:

Xiujuan Qu, email:

Yunpeng Liu, email:

Keywords: breast cancer, RANK, Cbl-b, metastasis, migration

Received: February 01, 2015 Accepted: May 22, 2015Published: June 08, 2015


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.

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