Spotlight on Exosomal Non-Coding RNAs in Breast Cancer: An In Silico Analysis to Identify Potential lncRNA/circRNA-miRNA-Target Axis.

Breast cancer (BC) has recently become the most common cancer type worldwide, with metastatic disease being the main reason for disease mortality. This has brought about strategies for early detection, especially the utilization of minimally invasive biomarkers found in various bodily fluids. Exosomes have been proposed as novel extracellular vesicles, readily detectable in bodily fluids, secreted from BC-cells or BC-tumor microenvironment cells, and capable of conferring cellular signals over long distances via various cargo molecules. This cargo is composed of different biomolecules, among which are the novel non-coding genome products, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and the recently discovered circular RNA (circRNA), all of which were found to be implicated in BC pathology. In this review, the diverse roles of the ncRNA cargo of BC-derived exosomes will be discussed, shedding light on their primarily oncogenic and additionally tumor suppressor roles at different levels of BC tumor progression, and drug sensitivity/resistance, along with presenting their diagnostic, prognostic, and predictive biomarker potential. Finally, benefiting from the miRNA sponging mechanism of action of lncRNAs and circRNAs, we established an experimentally validated breast cancer exosomal non-coding RNAs-regulated target gene axis from already published exosomal ncRNAs in BC. The resulting genes, pathways, gene ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis could be a starting point to better understand BC and may pave the way for the development of novel diagnostic and prognostic biomarkers and therapeutics.

A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer.

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.