Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype associated with a poor prognosis. The mechanism involved in TNBC progression remains largely unknown. To date, there are no effective therapeutic targets for this tumor subtype. In this study, by performing quantitative proteomic analyses in highly metastatic and parental breast cancer cell line, we found that RAB1B, a member of the RAS oncogene family, was significantly down-regulated in highly metastatic breast cancer cells. Moreover, down-regulation of RAB1B was also found to promote the proliferation and migration of TNBC cells in vitro and in vivo. Mechanistically, loss of RAB1B resulted in elevated expression of TGF-β receptor 1 (TβR1) through decreased degradation of ubiquitin, increased levels of phosphorylated SMAD3 and TGF-β-induced epithelial-mesenchymal transition (EMT). Furthermore, low RAB1B expression correlated with poor prognosis in breast cancer patients. Taken together, our findings reveal that RAB1B acts as a metastasis suppressor in TNBC by regulating the TGF-β/SMAD signaling pathway and RAB1B may serve as a novel biomarker of prognosis and the response to anti-tumor therapeutics for patients with TNBC.
Highlights
Triple-negative breast cancer (TNBC) is an invasive type of breast carcinoma that lacks expression of the estrogen receptor (ER) and progesterone receptor (PR) as well as human epidermal growth factor receptor 2 (HER2) amplification
RAB1B expression is down-regulated in highly metastatic breast cancer cells
Using the iTRAQ labeling method in our model system, we found that RAB1B was significantly downregulated in MDA-MB-231HM compared with MDAMB-231 cells (Figure 1A, 1B)
Summary
Triple-negative breast cancer (TNBC) is an invasive type of breast carcinoma that lacks expression of the estrogen receptor (ER) and progesterone receptor (PR) as well as human epidermal growth factor receptor 2 (HER2) amplification. TNBCs constitute approximately 10-17% of all invasive breast carcinomas and tend to more frequently affect younger patients [1,2,3,4,5,6]. Due to the heterogeneity of this disease and the absence of well-defined molecular targets [7,8,9], the treatment of TNBC has remained challenging. There is an urgent need for useful biomarkers that can predict the metastatic potential of TNBC and serve as prognostic indicators or targets for treatment
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