A large number of etiological factors and the complexity of breast cancers present challenges for prevention and treatment. Recently, the emergence of microRNAs (miRNAs) as cancer biomarkers has added an extra dimension to the ‘molecular signatures’ of breast cancer. Bioinformatic analyses indicate that each miRNA can regulate hundreds of target genes and could serve functionally as ‘oncogenes’ or ‘tumour suppressor’ genes, and co-ordinate multiple cellular processes relevant to cancer progression. A number of studies have shown that miRNAs play important roles in breast tumorigenesis, metastasis, proliferation and differentiation of breast cancer cells. This review provides a comprehensive overview of miRNAs with established functional relevance in breast cancer, their established target genes and resulting cellular phenotype. The role and application of circulating miRNAs in breast cancer is also discussed. Furthermore, we summarize the role of miRNAs in the hallmarks of breast cancer, as well as the possibility of using miRNAs as potential biomarkers for detection of breast cancer.

microRNAs in breast cancer: regulatory roles governing the hallmarks of cancer

microRNAs (miRNAs) stably exist in circulating blood and are encapsulated in extracellular vesicles such as exosomes. The aims of this study were to identify which exosomal miRNAs are highly produced from epithelial ovarian cancer (EOC) cells, to analyze whether serum miRNA can be used to discriminate patients with EOC from healthy volunteers, and to investigate the functional role of exosomal miRNAs in ovarian cancer progression. Exosomes were collected from the culture media of serous ovarian cancer cell lines, namely TYK-nu and HeyA8 cells. An exosomal miRNA microarray revealed that several miRNAs including miR-99a-5p were specifically elevated in EOC-derived exosomes. Expression levels of serum miR-99a-5p in 62 patients with EOC, 26 patients with benign ovarian tumors, and 20 healthy volunteers were determined by miRNA quantitative reverse transcription-polymerase chain reaction. To investigate the role of exosomal miR-99a-5p in peritoneal dissemination, neighboring human peritoneal mesothelial cells (HPMCs) were treated with EOC-derived exosomes and then expression levels of miR-99a-5p were examined. Furthermore, mimics of miR-99a-5p were transfected into HPMCs and the effect of miR-99a-5p on cancer invasion was analyzed using a 3D culture model. Proteomic analysis with the tandem mass tag method was performed on HPMCs transfected with miR-99a-5p and then potential target genes of miR-99a-5p were examined. The serum miR-99a-5p levels were significantly increased in patients with EOC, compared with those in benign tumor patients and healthy volunteers (1.7-fold and 2.8-fold, respectively). A receiver operating characteristic curve analysis showed with a cut-off of 1.41 showed sensitivity and specificity of 0.85 and 0.75, respectively, for detecting EOC (area under the curve = 0.88). Serum miR-99a-5p expression levels were significantly decreased after EOC surgeries (1.8 to 1.3, p = 0.002), indicating that miR-99a-5p reflects tumor burden. Treatment with EOC-derived exosomes significantly increased miR-99a-5p expression in HPMCs. HPMCs transfected with miR-99a-5p promoted ovarian cancer invasion and exhibited increased expression levels of fibronectin and vitronectin. Serum miR-99a-5p is significantly elevated in ovarian cancer patients. Exosomal miR-99a-5p from EOC cells promotes cell invasion by affecting HPMCs through fibronectin and vitronectin upregulation and may serve as a target for inhibiting ovarian cancer progression.

/pdf/exosomal-mir-99a-5p-is-elevated-in-sera-of-ovarian-cancer-15b1fq9kpi.pdf

Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion by increasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cells

Increasing evidences revealed that microRNAs (miRNAs) play critical roles in important biological processes. The identification of disease-related miRNAs is critical to understand the molecular mechanisms of human diseases. Most existing computational methods require diverse features to predict miRNA-disease associations. However, diverse features are not available for all miRNAs or diseases. In addition, most methods can't predict links for miRNAs or diseases without association information. In this paper, we propose a fast linear neighborhood similarity-based network link inference method, named FLNSNLI, to predict miRNA-disease associations. First, known miRNA-disease associations are formulated as a bipartite network, and miRNAs (or diseases) are expressed as association profiles. Second, miRNA-miRNA similarity and disease-disease similarity are calculated by fast linear neighborhood similarity measure and association profiles. Third, the label propagation algorithm is respectively implemented on two sides to score candidate miRNA-disease associations. Finally, FLNSNLI adopts the weighted average strategy and makes predictions. Moreover, we develop a link complementing approach, and extend FLNSNLI to predict links for miRNAs (or diseases) without known associations. In computational experiments, FLNSNLI produces high-accuracy performances, and outperforms other state-of-the-art methods. More importantly, FLNSNLI requires less information but performs well. Case studies on three popular diseases show that FLNSNLI is useful for the microRNA-disease association prediction.

A Fast Linear Neighborhood Similarity-Based Network Link Inference Method to Predict MicroRNA-Disease Associations

mTOR inhibition and p53 activation, microRNAs: The possible therapy against pandemic COVID-19

Objectives
miR-99a has been reported to function as a tumour suppressor in breast cancer. However, its role in the regulation of breast cancer stem cell (CSC) phenotype has up to now remained unknown.

Materials and methods
In this study, we isolated the side population (SP) cells by staining cultured MCF-7 and MDA-MB-231 cells with fluorescent DNA-binding dye Hoechst 33342, then by flow cytometric sorting. Next, we detected expression of miR-99a in the SP cells compared to non-SP cells using real-time PCR, and explored effects of miR-99a on the CSC phenotype of the breast cancer cells, including sphere formation, self-renewal, tumourigenicity and cell migratory capability.

Results
We found that expression of miR-99a was down-regulated in the SP cells compared to non-SP cells. Restoration of expression of miR-99a inhibited cell migration and invasion, reduced sphere formation of breast SP cells in vitro, and suppressed tumour growth in vivo. Finally, bioinformatic prediction suggested the oncogene, mammalian target of rapamycin (mTOR) – a downstream effector of the PI3K/AKT signalling pathway, was a target gene of miR-99a in SP cells. Further, quantitative RT-PCR and western blot assays identified that overexpression of miR-99a suppressed expression of mTOR and its downstream gene, HIF-1α.

Conclusion
Collectively, these data suggest that miR-99a reversed the breast cancer malignant CSC phenotype, probably by targeting the mTOR signalling pathway.

/pdf/mir-99a-directly-targets-the-mtor-signalling-pathway-in-5gd1chyyzb.pdf

miR‐99a directly targets the mTOR signalling pathway in breast cancer side population cells

MicroRNAs (miRNAs) play an important role in human tumorigenesis as oncogenes or tumor suppressors miR-99a has been reported as a tumor suppressor gene in various cancers in humans However, only limited information about the function of miR-99a in human breast cancers is available Here we investigated the expression of miR-99a in breast cancer tissue specimens and its antitumor activity in breast cancer cells We initially identified that the expression of miR-99a was significantly reduced in four breast cancer cell lines More importantly, we found downregulation of miR-99a in breast cancer specimens from ten different patients We then analyzed the mechanism of miR-99a in inhibiting tumorigenesis Cell-based assays that showed overexpression of miR-99a not only reduced breast cancer cell viability by inducing accumulation of cells at sub-G1 phase and cell apoptosis, but also inhibited tumorigenicity in vivo As a critical miR-99a target, we have shown that the function of mammalian target of rapamycin (mTOR) was greatly inhibited by miR-99a-based Luciferase report assay; overexpression of miR-99a reduced the expression of mTOR and its downstream phosphorylated proteins (p-4E-BP1 and p-S6K1) Similar to restoring miR-99a expression, mTOR downregulation suppressed cell viability and increased cell apoptosis, whereas restoration of mTOR expression significantly reversed the inhibitory effects of miR-99a on the mTOR/p-4E-BP1/p-S6K1 signal pathway and the miR-99a antitumor activity In clinical specimens and cell lines, mTOR was commonly overexpressed and its protein levels were statistically inversely correlated with miR-99a expression Taken together, these results have demonstrated that miR-99a antitumor activity is achieved by targeting the mTOR/p-4E-BP1/p-S6K1 pathway in human breast cancer cells This study suggests a potential therapeutic strategy to effectively control breast cancer development

/pdf/mir-99a-antitumor-activity-in-human-breast-cancer-cells-1wjm8o8ozh.pdf

MiR-99a antitumor activity in human breast cancer cells through targeting of mTOR expression.

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MiR-99a antitumor activity in human breast cancer cells through targeting of mTOR expression.