In-silico Elucidation of the Role of ABC-Transporter Genes Expression Regulation by OncomiRs (miR-21, miR-15, and miR-let-7) in Drug Efflux and Chemoresistance in Breast Cancer

Abstract

Breast cancer is the most common and aggressive malignancy in females with a high prevalence rate of 77.9 million worldwide. Chemotherapy and tyrosine kinase inhibitors have been used to treat invasive and malignant tumors; however, invasive tumors have showed resistance to conventional therapies. ABC transporters play a crucial role in breast cancer due to their chemo-resistance and drug efflux abilities. Additionally, chemo-resistant roles of ABC transporters have been reported in several cancers such as cervical cancer, colon cancer, esophageal squamous cell carcinoma, glioma and HCC. The goal of this study was to identify the tumor suppressor role of miR-21, miR-15 and miR-let-7 to chemo-resistant genes majorly ABCA1, ABCB1 and ABCC1 in breast cancer. TargetScan, miRWalk, and miRDB were employed to predict microRNA-mRNA interactions. MC-Sym and RNAComposer were utilized for the tertiary structure prediction of shortlisted miRNAs and mRNAs. For molecular docking and visualization, HDOCK and PyMOL were employed. The present study identified 10, 7 and 13 interactions between microRNAs (miR-21, miR-15, and miR-let-7) and oncogenes (ABCA1, ABCB1, ABCC1) through miRWalk, miRDB and TargetScan respectively. RNA22 predicted the binding sites of microRNAs such as 22 miR-21, 11 miR-15 and 58 miR-let-7 on ABCA1, ABCB1 and ABCC1, respectively. Out of multiple docked complexes, the top 3 were shortlisted for visualization based on maximum confidence score and least binding affinity. The present study identifies the interactions of two novel (miR-15a-5p and let-7c-5p) microRNAs with ABCA1, ABCB1 and ABCC1 regions due to their maximum interactions. The findings of this research may help in developing miRNA drugs that could target ABC transporters specifically ABCA1, ABCB1 and ABCC1 to inhibit increased drug efflux and chemoresistance in breast cancer.