Analyzing the role of Non-Coding RNA in Conferring Tamoxifen and Trastuzumab-Resistant Breast Cancer

Abstract

Reports from WHO (2020) indicate that breast cancer is the prevalent cause of mortality amongst females across the globe. Breast cancer (BC) is a heterogeneous disease and is histologically classified into Luminal A, Luminal B, HER2+, and Triple Negative Breast Cancer (TNBC). Currently, the treatment regime of breast cancer is dependent on the presence of hormone receptors – Estrogen (ER), Progesterone (PR), and Human epidermal growth factor (Her2/neu). 60-70% of BC patients are diagnosed as ER-positive and are treated with selective estrogen receptor modulators (SERMs), chiefly Tamoxifen whereas, 15-20% of the patients show HER2 positive and are managed mainly by Trastuzumab. Tamoxifen and Trastuzumab is a universally accepted drug that is cost-effective and with minimum side effects. Resistance to treatment modalities is a major obstacle in the therapeutic regime from which 20-30% of tumors develop resistance due to tamoxifen while 2-3% of the tumors acquire resistance to Herceptin. Hence, it has become the need of the hour to identify the underlying mechanisms that cause tamoxifen and Herceptin resistance in ER+ tumors and HER2 + tumors respectively. Studies now focus on deciphering the role of non-coding RNAs in causing resistance in breast cancer. Non-coding RNAs are classified into small non-coding RNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). We are focusing on microRNAs that are playing role in the resistance and by using bioinformatics tools we have identified miRNA as a therapeutic target which was later validated by in-vitro analysis. Our study identified that the upregulation of miR-190b and miR-375 and downregulation of miR-135b are responsible for causing tamoxifen resistance in breast cancer patients. While miR-1276 was found to be downregulated in trastuzumab resistance breast cancer cell lines. Further, we validated miR-375 in an acquired tamoxifen-resistant MCF-7 breast cancer cell line. By in vitro analysis, it was observed that miR-375 was upregulated in the tamoxifen-resistant breast cancer cell line as compared to untreated cells.