Screening of Immune-Related Genes and Predicting the Immunotherapeutic Effects of Formononetin in Breast Cancer: A Bioinformatics Analysis

Abstract

Objective. Immunotherapy is a promising breast cancer treatment. Nonetheless, tumor heterogeneity and the interaction between immune cells in the tumor microenvironment limit its effectiveness. Formononetin - extracted from the Chinese medicinal plant Astragalus membranaceus - can inhibit tumor growth, induce apoptosis and angiogenesis, and reverse multidrug resistance. However, its efficacy and mechanism of action on the immune cells in breast cancer remain unclear. Here, we screened immune-related genes of breast cancer to determine the potential of formononetin as a therapeutic. Methods. GSE103512 and GSE139038 breast cancer microarray data and immune-related gene data were obtained from the GEO and ImmPort databases, respectively, to analyze the differentially expressed immune-related genes (IRGs) in breast cancer tissues compared with normal breast tissues. Protein-protein interaction (PPI) analysis was performed using the STRING database to screen differentially expressed IRGs based on the topological parameters. The Kaplan-Meier test was applied to detect differentially expressed IRGs associated with breast cancer survival, and the interaction of formononetin with differentially expressed IRGs was analyzed using molecular docking. Finally, the relationship between differentially expressed IRGs and breast cancer immune cell infiltration was analyzed using the TIMER2.0 database. Results. A total of 29 differentially expressed IRGs of breast cancer were screened through GEO and ImmPort databases and 10 key differentially expressed IRGs based on the topological parameters from the PPI network. Among these, CXCL12, ESR1, IGF1, and FOS were associated with breast cancer survival. Furthermore, IGF1, ESR1, and CXCL12 were found to have stable binding sites for formononetin. These genes were associated with substantial immune cell infiltration in breast cancer tissues. Conclusion. In conclusion, formononetin may exert antitumor effects by acting on CXCL12, ESR1, and IGF1 and may have a potential synergistic effect with immune checkpoint inhibitors.