In this study, we observed that VDAC1 was elevated while Cytc was decreased in breast carcinoma patients compared with benign breast lesions. VDAC1 protein expression was conversely correlated with Cytc in BC, especially in TNBC. Both high VDAC1 and low Cytc protein expression had significant positive correlation with poor prognosis. High VDAC1 expression also represented an independent predictor for poor prognosis of TNBC.
VDAC1 participates in cancer metabolism via its modulatory roles in the transport of various metabolites. In many types of cancer, the interaction of VDAC1 with HK, especially HK II, directly accesses to mitochondrial ATP for phosphorylation of glucose to glucose-6-phosphate and contributes to the cancer cells unrestricted growth and the inhibiting of apoptosis[19, 32]. VDAC1 has been found to be involved in tumor proliferation, migration, metastasis and invasion, and acts as a controvertial role in the prognosis of different malignant tumors. In uterine cervical cancer, VDAC1 was associated with exhibited deeper stromal invasion, larger tumor size, higher recurrence and poorer overall survival. Conversely, in Cholangiocellular Carcinoma, VDAC1 levels were inversely correlated with cancer stage classification and lower VDAC1 was present in patients with lymph node involvement and reduced survival. These conflicting consequences demonstrate the differential effects of VDAC1 expression in different kinds of cancer and may need further exploration. In the present study, 219 cases of primary invasive breast cancer tissues were collected and it was found that VDAC1 protein was primarily located in the membrane of tumor cells in BC tissues. The relative expression of VDAC1 protein in breast cancer solid tumors was significantly higher than that in benign breast lesions, and high expression of VDAC1 protein correlated with advanced TNM stage, higher histological grade, recurrence, lymph node metastasis and HER2 gene amplification, thereby suggesting that high VDAC1 expression may play a role in promoting tumorigenesis and progression of BC. Interestingly, our present results were consistent with the reports in pancreatic cancer and colorectal cancer, which indicated VDAC1 expression was upregulated in tumor and promoted the growth and invasion of cancer cells. Furthermore, by the multivariate analysis, we found that overexpression of VDAC1 protein in BC tissues could be as an independent poor prognostic factor. Consistent with this result, Chih-Hsien and Eiran’s studies also showed that high expression of VDAC1 was correlated with poorer prognosis in uterine cervical cancer and hepatocellular carcinoma [16, 17]. Therefore, these data suggest that VDAC1 has the potential of being a poor prognostic marker in BC. As TNBC showed more progressively malignant manifestation with worse clinical outcomes and is mostly insensitive to drug treatment, we next explored the correlation of VDAC1 expression with the prognosis of TNBC. Amazingly, our result demonstrated that high VDAC1 protein was also associated with reduced 5-DFS and acted as an independent predictor of poor prognosis in TNBC, suggesting more potential use of VDAC1 should be exploited in prognostic marker and therapeutic target.
Cytc release from mitochondria is the driving force for apoptosome leading to apoptotic cell death in several malignant tumor, and VDAC1 has been widely reported to be interacted with pro- or anti-apoptotic proteins such as Bcl-2 and HK whereby mediating the release of Cytc. In many types of cancer cells, when HK2 binds to VDAC1, the interaction between VDAC1 and Bcl-2 protein family will be blocked, resulting in a decrease in Cytc release, thus protecting tumor cells from apoptosis. In our present study, we observed that VDAC1 protein expression was inversely associated with Cytc in BC, especially in TNBC. Furthermore, Cytc was lower expressed in BC compared with benign breast lesions and low expression of Cytc was correlated with higher histological grade, ER status, PR status and recurrence. A similar correlation was found in prostate cancer which Cytc deficiency contributed to tumor invasiveness and faster recurrence. Importantly, we also found that decreased expression of Cytc was an independent prognostic factor in breast cancer solid tumors and played a pivotal role in the poorer 5-DFS of that cohort of BC patients. As a result, contrary to VDAC1, Cytc has the potential to be an improved prognostic marker in BC.
It should be acknowledged that there are also some limitations in this study. Firstly, due to the limited number of patients in this study, a larger cohort is required to explore the role and mechanism of VDAC1 and Cytc in the progression of breast cancer in the future. Secondly, more investigations need to be conducted to explore the mechanisms by which VDAC1 reduce Cytc release in BC. Thirdly, the prognostic significance of VDAC1 in breast cancer was discussed only at histological level. The exact role of VDAC1 in breast cancer, especially in TNBC, still needs to be evaluated in follow-up mechanistic investigations. Fourthly, our study evaluated prognosis by 5-DFS rather than OS. Since DFS sometimes not correlated with OS, the influence of VDAC1 expression on OS is still a topic for future research.