Network Pharmacological Analysis Identifies the Curcumin Analog CCA-1.1 Targeting Mitosis Regulatory Process in HER2-Positive Breast Cancer

Abstract

Recent studies have demonstrated that a curcumin derivative, namely, chemoprevention-curcumin analog 1.1 (CCA-1.1), impedes the proliferation of breast cancer (BC) cells, including luminal, human epidermal growth factor 2 (HER2)-overexpressed, and triple-negative BC cells. We analyzed the possible target of action of CCA-1.1, particularly in BC cells with HER2 amplification, using bioinformatics analysis. The differentially expressed genes (DEGs) of HER2-positive BC were retrieved from The Cancer Genome Atlas–Breast Invasive Carcinoma data (via UALCAN). Using the SMILE similarity feature, we used three web-based tools (Swiss Target Prediction, BindingDB, and TargetNet) to predict the potential target of CCA-1.1. The functional annotation and network enrichment were processed in WebGestalt. The alteration of selected genes was observed in CBioPortal. The protein–protein interaction network was constructed in STRING and then ranked based on the degree score using the Cytohubba feature in Cytoscape. The survival analysis of hub genes was determined in Gene Expression Profiling Interactive Analysis 2 (GEPIA2) with selection for HER2-positive BC cases only. The correlation between hub genes and tumor-infiltrating immune markers was determined using TIMER web tools. The pathway network analysis highlighted the cell cycle regulation in mitosis affected by signaling amid putative CCA-1.1 targets. We identified eight potential genes, including aurora A kinase (AURKA), aurora B kinase (AURKB), polo-like kinase 1, TPX2 microtubule nucleation factor, kinesin-like protein KIF11, maternal embryonic leucine zipper kinase, cyclin-dependent kinase 1 (CDK1), and serine/threonine-protein kinase Chk1 (CHEK1), that may inhibit mitosis regulation in response to CCA-1.1 treatment. Several potential markers (AURKB, AURKA, CDK1, and CHEK1) were correlated with immune cell infiltration markers. CCA-1.1 may regulate mitosis to induce cell cycle arrest and lead to cell death. The predicted targets of CCA-1.11 gave insights into the potency of CCA-1.1 to be applied with immunotherapy. Further validation of the data presented in the study is essential to develop CCA-1.1 for BC treatment.