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Potential miRNAs for miRNA-Based Therapeutics in Breast Cancer.

ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs that can post-transcriptionally regulate the genes involved in critical cellular processes. The aberrant expressions of oncogenic or tumor suppressor miRNAs have been associated with cancer progression and malignancies. This resulted in the dysregulation of signaling pathways involved in cell proliferation, apoptosis and survival, metastasis, cancer recurrence and chemoresistance. In this review, we will first (i) provide an overview of the miRNA biogenesis pathways, and in vitro and in vivo models for research, (ii) summarize the most recent findings on the roles of microRNAs (miRNAs) that could potentially be used for miRNA-based therapy in the treatment of breast cancer and (iii) discuss the various therapeutic applications.

SUBMITTER: Wong JS

PROVIDER: S-EPMC7549352 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Potential miRNAs for miRNA-Based Therapeutics in Breast Cancer.

Wong Jun Sheng JS Cheah Yoke Kqueen YK

Non-coding RNA 20200713 3

MicroRNAs (miRNAs) are small non-coding RNAs that can post-transcriptionally regulate the genes involved in critical cellular processes. The aberrant expressions of oncogenic or tumor suppressor miRNAs have been associated with cancer progression and malignancies. This resulted in the dysregulation of signaling pathways involved in cell proliferation, apoptosis and survival, metastasis, cancer recurrence and chemoresistance. In this review, we will first (i) provide an overview of the miRNA biog ...[more]

PMID: 32668603

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Project description:Network-based computational method, with the emphasis on biomolecular interactions and biological data integration, has succeeded in drug development and created new directions, such as drug repositioning and drug combination. Drug repositioning, that is finding new uses for existing drugs to treat more patients, offers time, cost and efficiency benefits in drug development, especially when in silico techniques are used. MicroRNAs (miRNAs) play important roles in multiple biological processes and have attracted much scientific attention recently. Moreover, cumulative studies demonstrate that the mature miRNAs as well as their precursors can be targeted by small molecular drugs. At the same time, human diseases result from the disordered interplay of tissue- and cell lineage-specific processes. However, few computational researches predict drug-disease potential relationships based on miRNA data and tissue specificity. Therefore, based on miRNA data and the tissue specificity of diseases, we propose a new method named as miTS to predict the potential treatments for diseases. Firstly, based on miRNAs data, target genes and information of FDA (Food and Drug Administration) approved drugs, we evaluate the relationships between miRNAs and drugs in the tissue-specific PPI (protein-protein) network. Then, we construct a tripartite network: drug-miRNA-disease Finally, we obtain the potential drug-disease associations based on the tripartite network. In this paper, we take breast cancer as case study and focus on the top-30 predicted drugs. 25 of them (83.3%) are found having known connections with breast cancer in CTD (Comparative Toxicogenomics Database) benchmark and the other 5 drugs are potential drugs for breast cancer. We further evaluate the 5 newly predicted drugs from clinical records, literature mining, KEGG pathways enrichment analysis and overlapping genes between enriched pathways. For each of the 5 new drugs, strongly supported evidences can be found in three or more aspects. In particular, Regorafenib (DB08896) has 15 overlapping KEGG pathways with breast cancer and their p-values are all very small. In addition, whether in the literature curation or clinical validation, Regorafenib has a strong correlation with breast cancer. All the facts show that Regorafenib is likely to be a truly effective drug, worthy of our further study. It further follows that our method miTS is effective and practical for predicting new drug indications, which will provide potential values for treatments of complex diseases.

Project description:Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of "central dogma" of simplified reductionist transcription and single gene-phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.

Dataset Information

Potential miRNAs for miRNA-Based Therapeutics in Breast Cancer.

Publications

Potential miRNAs for miRNA-Based Therapeutics in Breast Cancer.

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