Abstract
MicroRNA-210-3p is the most prominent hypoxia regulated microRNA, and it has been found significantly overexpressed in different human cancers. We performed the expression analysis of miR-210-3p in a retrospective cohort of breast cancer patients with a median follow-up of 76 months (n = 283). An association between higher levels of miR-210-3p and risk of disease progression (HR: 2.13, 95%CI: 1.33-3.39, P = 0.002) was found in the subgroup of patients treated with Epirubicin and Cyclophosphamide followed by Docetaxel. Moreover, a cut off value of 20.966 established by ROC curve analyses allowed to discriminate patients who developed distant metastases with an accuracy of 85% at 3- (AUC: 0.870, 95%CI: 0.690-1.000) and 83% at 5-years follow up (AUC: 0.832, 95%CI: 0.656–1.000). Whereas the accuracy in discriminating patients who died for the disease was of 79.6% at both 5- (AUC: 0.804, 95%CI: 0.517–1.000) and 10-years (AUC: 0.804. 95%CI: 0.517–1.000) follow-up. In silico analysis of miR-210-3p and Docetaxel targets provided evidence for a putative molecular cross-talk involving microtubule regulation, drug efflux metabolism and oxidative stress response. Overall, our data point to the miR-210-3p involvement in the response to therapeutic regimens including Docetaxel in sequential therapy with anthracyclines, suggesting it may represent a predictive biomarker in breast cancer patients.
Highlights
Breast cancer (BC) is the most frequent malignancy that develops in women worldwide and accounts for the highest rates of cancer-associated death
MiR-210-3p was shown to be up-regulated in triple-negative breast cancer (TNBC) compared to estrogen positive tumors[5,18], showing relevance even in this group where high levels of miR-210 were found correlating with a higher risk of recurrence under tamoxifen treatment[19]
When we compared cancer cases classified on the basis of surrogate molecular classification (Luminal A, Luminal B, HER2-amplified and Triple Negative), the Triple Negative subgroup showed the highest level of miR210 expression, followed by Luminal B tumours, whereas Luminal A, and HER2-amplified tumours showed the lowest expression levels (P = 0.0137)
Summary
Breast cancer (BC) is the most frequent malignancy that develops in women worldwide and accounts for the highest rates of cancer-associated death. MicroRNAs have www.nature.com/scientificreports been attracting much attention due to their frequent dysregulation in human cancers and, more importantly, their association with the clinicopathological parameters, the latter supporting their emergence as a new class of molecular biomarkers In this regard, several miRNA profiles of breast cancer have been established by microarray or next-generation sequencing (NGS), and the resulting miRNA signatures have been correlated to the typical clinicopathological and prognostic characteristics including tumor size, lymph-node invasion, receptors status, and resistance to chemotherapy[3,4,5,6]. Recent findings by Bar I. et al.[20] demonstrated miR-210 tends to localize and be expressed both in epithelial cancer cells and in the tumor microenvironment (TME) of TNBC samples, in inflammatory cells where it is likely to be regulated by a mechanism independent of HIF-1α20 In spite of these data, some discrepancies about miR-210-3p significance from a clinical standpoint do exist. These discrepancies spurred us to perform a miR-210-3p expression analysis in our large cohort of breast cancer patients with a long-term follow-up in the attempt to clarify the correlation of miR-210-3p with clinical parameters and help understand if miR-210-3p holds promise as biomarker in breast cancer
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