Clinical Identification of Dysregulated Circulating microRNAs and Their Implication in Drug Response in Triple Negative Breast Cancer (TNBC) by Target Gene Network and Meta-Analysis

• Published in: Genes Vol. 12; no. 4; p. 549
• Main Authors: Qattan, Amal, Al-Tweigeri, Taher, Alkhayal, Wafa, Suleman, Kausar, Tulbah, Asma, Amer, Suad
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.04.2021; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Breast cancer; Cancer therapies; Cell cycle; chemoresistance; Chemotherapy; circulating miRNA; DNA damage; Drug interaction; Drug resistance; Enzyme inhibitors; Epidermal growth factor receptors; Forkhead protein; Growth factors; Medical prognosis; Meta-analysis; MicroRNAs; miRNA; Mortality; PD-1 protein; PD-L1 protein; Pharmacogenomics; Plasma; Precision medicine; Protein-tyrosine kinase; theranostic markers; TOR protein; triple-negative breast cancer; Tumors; Wnt protein; Germany; circulating miRNA; chemoresistance; triple-negative breast cancer; theranostic markers
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes12040549

Resistance to therapy is a persistent problem that leads to mortality in breast cancer, particularly triple-negative breast cancer (TNBC). MiRNAs have become a focus of investigation as tissue-specific regulators of gene networks related to drug resistance. Circulating miRNAs are readily accessible non-invasive potential biomarkers for TNBC diagnosis, prognosis, and drug-response. Our aim was to use systems biology, meta-analysis, and network approaches to delineate the drug resistance pathways and clinical outcomes associated with circulating miRNAs in TNBC patients. MiRNA expression analysis was used to investigate differentially regulated circulating miRNAs in TNBC patients, and integrated pathway regulation, gene ontology, and pharmacogenomic network analyses were used to identify target genes, miRNAs, and drug interaction networks. Herein, we identified significant differentially expressed circulating miRNAs in TNBC patients (miR-19a/b-3p, miR-25-3p, miR-22-3p, miR-210-3p, miR-93-5p, and miR-199a-3p) that regulate several molecular pathways (PAM (PI3K/Akt/mTOR), HIF-1, TNF, FoxO, Wnt, and JAK/STAT, PD-1/PD-L1 pathways and EGFR tyrosine kinase inhibitor resistance (TKIs)) involved in drug resistance. Through meta-analysis, we demonstrated an association of upregulated miR-93, miR-210, miR-19a, and miR-19b with poor overall survival outcomes in TNBC patients. These results identify miRNA-regulated mechanisms of drug resistance and potential targets for combination with chemotherapy to overcome drug resistance in TNBC. We demonstrate that integrated analysis of multi-dimensional data can unravel mechanisms of drug-resistance related to circulating miRNAs, particularly in TNBC. These circulating miRNAs may be useful as markers of drug response and resistance in the guidance of personalized medicine for TNBC.