Drug repositioning based on gene expression data for human HER2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents approximately 15-30% of all invasive breast cancers. Despite the recent advances in therapeutic practices of HER2 subtype, drug resistance and tumor recurrence still have remained as major problems. Drug discovery is a long and difficult process, so the aim of this study is to find potential new application for existing therapeutic agents. Gene expression data for breast invasive carcinoma were retrieved from The Cancer Genome Atlas (TCGA) database. The normal and tumor samples were analyzed using Linear Models for Microarray Data (LIMMA) R package in order to find the differentially expressed genes (DEGs). These genes were used as entry for the library of integrated network-based cellular signatures (LINCS) L1000CDS2 software and suggested 24 repurposed drugs. According to the obtained results, some of these drugs including vorinostat, mocetinostat, alvocidib, CGP-60474, BMS-387032, AT-7519, and curcumin have significant functional similarity and structural correlation with FDA-approved breast cancer drugs. Based on the drug-target network, which consisted of the repurposed drugs and their target genes, the aforementioned drugs had the highest degrees. Moreover, the experimental approach verified curcumin as an effective therapeutic agent for HER2 positive breast cancer. Hence, our work suggested that some repurposed drugs based on gene expression data can be noticed as potential drugs for the treatment of HER2-positive breast cancer.

Rapid screening of drug candidates against EGFR/HER2 signaling pathway using fluorescence assay.

Over the recent decade, the calcium-based assays have gained much popularity in order to discover new drugs. Since breast cancer is the second cause of death in the female population, rapid and effective methods are needed to screen drug compounds with fewer side effects. Human epidermal growth factor receptor 2 (HER2) increases intracellular free Ca2+ on its signaling pathways. In the present study, BT474 cell line, which overexpresses HER2 receptor, was selected and using fura-2-AM, intracellular Ca2+ release was investigated. The changes in the concentration of intracellular Ca2+ were evaluated by variation in the amount of fluorescence intensity. In the presence of epidermal growth factor (EGF), an increase in fluorescence intensity was observed so that after 20 min it raised to the maximum level. After treatment of BT474 cells by lapatinib, as a tyrosine kinase inhibitor (TKI), the signaling pathway of EGFR/HER2 heterodimer was significantly inhibited, which resulted in a decrease in Ca2+ entry into the cytoplasm and fluorescence emission decreased. The IC50 value for the effect of lapatinib on BT474 cells was 113.2 nmol/L. Our results suggest this method is a simple, efficient and specific approach and can potentially be useful for screening new drug candidates against EGFR/HER2 heterodimer signaling pathways. Graphical abstract ᅟ.