Up to date, an effective therapeutic for breast cancer has been lacking in the clinical3,15. Despite the different treatments, including surgery, radiotherapy, chemotherapy, and endocrine therapy have been routinely applied for breast cancer3,16,17. However, a part of patients will still get recurrence and metastasis. Thus, additional studies on therapeutic targets are still needed to reveal new prognostic markers are of great importance. In our previous study, we found that the MEOX2 expression was significantly repressed in breast cancer. The mRNA level of MEOX2 in breast cancer cells MCF-7 and SUM159PT was significantly lower than that in human mammary epithelial cells MCF-10A. However, there are still no reports on associations between MEOX2 expression and clinicopathological features of breast cancer.
In this study, we firstly revealed MEOX2 is associated with clinicopathological features and prognosis in breast cancer. The results showed that the MEOX2 mRNA level was obviously higher in normal breast tissues than in breast cancer tissues. Moreover, low MEOX2 expression was associated with ER-negative, PR-negative, HER2 positive, and p53 mutation subtypes of breast cancer. Indeed, MEOX2 expression was lower in a triple-negative group. The decreasing of MEOX2 expression was significantly correlated with the decreased overall survival days by KM Plotter analysis. Furthermore, we used a high-throughput tissue microarray to verify the above results by immunohistochemical staining, which showed MEOX2 was detected in 74.1% of the total 135 breast cancer tissues, including 74 cases of low expression and 61 cases of high expression. MEOX2 was associated with low histological grade and negatively correlated with Ki67 expression level. Low MEOX2 level implied the poorer prognosis of all breast cancer patients and subtypes of Luminal A and Luminal B. Multivariate COX regression revealed that MEOX2 should be an independent prognostic factor in breast cancer.
MEOX2 was firstly discovered in VSMCs, and was cloned by Gorski et al. in 199318. It inhibited the proliferation and regulated the transition of vascular smooth muscle cells19,20. Furthermore, MEOX2 could impede endothelial cell angiogenesis by down-regulating the NF-kB downstream target genes via preventing the binding of NF-kB to its target. It activated p21 WAF1/ CIP1 transcription in vascular endothelial cells through direct interaction with upstream A T-rich s sequences to inhibit angiogenesis21,22. MEOX2 could also promote cellular senescence via up-regulating of cyclin dependent kinase inhibitors p16 and p218. Besides, TGF-b was reported to regulate MEOX2 expression in epithelial cells through Smad signaling23.
Notably, instead of a maladaptation role in vasculogenesis, MEOX2 promoted the development of vascular cells in endothelial colony forming cells (ECFCs), and enhanced network formation in DM pregnancies24. In Alzheimer’s disease, the MEOX2-induced effect on angiogenesis was biphasic, MEOX2 were anti-angiogenic at a high level, while proangiogenic at a moderate level25,26.
MEOX2 functions a dual role in tumor development and prognosis, however, its specific mechanism was still unclear. MEOX2 expression was significantly suppressed in liver cancer tissues. The decreased expression was associated with edmondson staging, vascular invasion, envelope invasion, and shorter overall survival time and disease-free survival, suggesting that it was an independent prognostic factor in liver cancer27,28. Compared with normal laryngeal tissue, MEOX2 expression in laryngeal carcinoma tissue was significantly lower. It was correlated with TNM stage, histological differentiation, and tumor grade. This was due to MEOX2 could inhibit cell viability and promote apoptosis by regulating apoptosis related factors and the PI3K/Akt pathway13. Loss of MEOX2 in Wilms Tumor may accelerate angiogenesis and augment signals in Wnt pathway29. In this way, MEOX2 was acted as a potential tumor suppressor gene.
On the other hand, MEOX2-GLI1 transcription axis in lung cancer was involved in the migration, diffusion, and resistance to cisplatin of cancer cells. MEOX2-GLI1 was related to poor overall survival in lung cancer patients. Accompanying by epigenetic events constituted, overexpression of MEOX2 might cause a new cancer drug resistance mechanism 30,31. Another study suggested that the MEOX2 level in lung cancer was decreased, it may be downregulated by DNA methylation32. In gastric cancer, the conclusion was contrary to that in lung cancer. Overexpression of E2F1 induced the down regulation of MEOX2, reducing the sensitivity of cells to anti-cancer drugs and inhibiting cell apoptosis. In addition, there were some other similar reports in glioma33,34, pancreas tumor35, and colon tumors36. Recently, different miRNAs have been found to regulate MEOX2 expression in cancers, such as miR-22137, miR-30138 and miR-301a28.
Our data got similar conclusions to the reports in liver cancer and laryngeal cancer. We confirmed that the decreasing of MEOX2 expression suggested a poor prognosis of breast cancer. Ki67 was a vital index to evaluate the proliferation of tumor cells, and it is inversely correlated with MEOX2 expression, which indicates that MEOX2 might inhibit the malignant behaviors of breast cancer cells.
However, our work also exists certain limitations. First, it was a retrospective analysis article, and the results might be affected by other factors. Secondly, the specific mechanisms of MEOX2 in breast cancer were not investigated, we only revealed an association of MEOX2 with clinicopathological features by immunohistochemical staining.
In conclusion, lower MEOX2 expression was related to tumor proliferation and could be a new diagnostic and prognostic biomarker of breast cancer.