title: 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.
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Yuee
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Yanju
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Ce
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011379:Prognosis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl
keywords: Cbl-b; RANK; breast cancer; metastasis; migration