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.

Amal Qattan,Taher Al-Tweigeri,Wafa Alkhayal,Kausar Suleman,Suad Amer,Asma Tulbah

doi:10.3390/genes12040549

Abstract

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.

Highlights

This article is an open access articleResistance to therapy is a persistent problem that leads to mortality in cancer patients.breast cancer typically responds well to platinum based first-line therapy, but recurs with a resistant phenotype in the majority of cases
A total of 127 individuals were analyzed in this study, including 34 healthy subjects and 93 breast cancer patients; 36 of those classified as having triple negative breast cancer (TNBC)
MiRNAs have been shown to target PTEN, to promote the expression of CDK and modify chemoresistance in cancer [47]. mTOR is involved in the PI3K/Akt signaling pathway, promoting proliferation and survival. miR-199a-3p, which we found to be significantly downregulated in TNBC, can target mTOR and c-Met, affecting sensitivity to doxorubicin [48]

Summary

Introduction

Breast cancer typically responds well to platinum based first-line therapy, but recurs with a resistant phenotype in the majority of cases. Forefront as tissue-specific regulators of entire gene networks related to drug resistance [1,2]. Dysregulation of complex genetic and functional networks by miRNAs are attractive mechanisms for therapeutic targeting to restore normal tissue function. MiRNAs are dysregulated in the tumor microenvironment and released into the bloodstream [3,4,5,6]. These circulating miRNAs are stable owing to structural resistance to RNases, making them amenable to applications as non-invasive markers of disease and drug response [7]

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