Rab27B, a regulator of vesicle exocytosis, has been suggested to function as an oncogene in ER-positive breast cell lines both in vitro and in vivo . However, without patients’ survival information, we could not investigate the effect of Rab27B expression on patient prognosis. We performed the present study to investigate the expression dynamics of Rab27B and their clinicopathologic/prognostic significance in BC patients. To the best of our knowledge, this is the first study investigating the expression of Rab27B in a large series of BC patients.
The previous study showed that Rab27B is upregulated in BC ; however, Dong et.al reported that the Rab27B expression level was lower in primary hepatocellular carcinoma than in matched adjacent tissues . Our results showed that both the mRNA and protein levels were upregulated in BCs compared with their NATs. Furthermore, we are first to report that expression levels of Rab27B appeared to increase with the magnitude of cancer progression: a significant increasing expression of Rab27B was observed from normal breast tissue, to FA, DCIS, and to invasive BC, metastatic LNs In our study, further correlation analysis revealed for the first time that high Rab27B expression was closely correlated with an aggressive phenotype of BC, including ascending pathologic grade, advanced clinical stage, and lymph node metastasis. These data, in agreement with data of the previous study , indicate that increased Rab27B expression corresponds to the progressive magnitude of BC and might facilitate the invasive/metastatic phenotypes of this malignancy, Rab27B is responsible for regulating many secretory mechanisms. Many studies have demonstrated that tumor cells use exosomes to communicate with surrounding tissues and immune cells, creating an immunosuppressive microenvironment for tumor progression [30–33]. Thus, we propose that Rab27B is associated with tumor progression because of its function as a transport vesicle.
It is well known that tumor invasion and metastases are responsible for most cancer-related mortality. As for invasive BC, the lymphatic system is the primary pathway to metastatic disease. For patients with lymph node metastasis, additional chemoradiation is required. Thus, identification of biomarkers that can be used to define the metastatic potential of BC may facilitate the development of appropriate therapeautic strategy earlier in the course of this cancer. In this study, we found that those with higher Rab27B expression are prone to have lymph node metastasis. We recommend that they be identified as patients at high risk in the clinic and that more radical therapy regimens should be delivered to them. Furthermore, the accuracy of predicting lymph node metastasis by examining Rab27B expression level (high vs. low) in our cohort is 60.7% (65/107). In light of these findings, we hypothesize that Rab27B may be a novel predictor of lymph node metastasis in BC patients. To address this issue, a further study in a larger cohort of BC patients is now underway.
As for the underlying mechanism involved in Rab27B-regulating BC invasive and metastasis potential, here we focused on the EMT process. During this process, epithelia cells lose their epithelia adherence, cell-cell contact and their polarity, and undergo remarkable remodeling of the cytoskeleton, all of which facilitate cell invasion and migration [34, 35]. Interestingly, our results demonstrated that BCs with Rab27B high expression displayed the enhanced expression of the mesenchymal markers vimentin and fibronectin, and decreased expression of the epithelial markers E-cadherin and β-catenin, suggesting an EMT process during Rab27B-regulating BC development. The acquisition of EMT characteristics may give these BC tumor cells a higher aggressive potential, resulting in the invasive and metastatic behavior. Thus we underscore that the EMT process might be a potential underlying mechanism in Rab27B-regulating BC invasion and metastasis. However, further study is underway to identify the special pathway involved in Rab27B mediated EMT process in BC.
Recently Rab27B was identified as a predictor of prognosis in HCC . With regard to the prognostic effect of Rab27B in BC, our findings show for the first time that BC patients with elevated Rab27B expression had worse survival outcomes than those expressing lower Rab27B, suggesting the clinical value of Rab27B in assessing the prognosis of BC patients. Furthermore, even after by stratified analysis, Rab27B could display a favorable prognosis value in each subgroup. Our findings strongly suggest that Rab27B may be a novel and important prognostic marker for BC patients.
It is noteworthy that the previous study found no Rab27B staining in ER-negative samples ; however, we detected positive staining in such samples. The difference may reflect differences in Rab27B status in the samples used in different studies, which obtained tissue samples from different populations. Furthermore, the previous study enrolled only 59 cases, whereas 221 are included in our study, leading to a more convincing result . Furthermore, in our enrolled cases, the prognostic significance of Rab27B expression was not confined to this group. These results confirm that the pro-oncogenic function of Rab27B is not ER-dependent. Thus, Rab27B could be adopted as a widely used biomarker in predicting patients’ survival. However, these results should be confirmed in a large, multicenter trial.