Identification of FPR3 as a unique biomarker for targeted therapy in the immune microenvironment of breast cancer
Abstract Background Immunotherapy is in the ascendant, but its use in the treatment of breast cancer remains limited. Thus, identification and evaluation of prognostic biomarkers of tissue microenvironment will reveal new immune-based therapeutic strategies for breast cancer. Methods Using in silico bioinformatic approach, we investigated the tumor microenvironmental and genetic factors related to breast cancer. We calculated the Immune score, Stromal score, Estimate score, Tumor purity, Tumor mutation burden (TMB), Mutant-allele tumor heterogeneity (MATH) of breast cancer patients from the Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm and Maftools. Weighted correlation network analysis (WGCNA) was used to identify gene patterns association with the Immune score. Then we use the MCODE plugin of Cytoscape to analyze the protein-protein interaction (PPI) network for mining the functional gene modules. Survival and Cox analysis was further performed to identify the key prognostic targets in immune microenvironment. Gene set enrichment analysis (GSEA) was utilized to explore the carcinogenic pathways associated with the target genes. Results Significant correlations between Immune/Stromal scores with breast cancer subtypes and tumor stages were established. Importantly, we found that the Immune score, but not the Stromal score, was significantly related to the patient's prognosis. WGCNA identified a pattern of gene function associated with Immune score, and that almost all of these genes (388 genes) are significantly upregulated in the higher Immune score group. PPI network analysis revealed the enrichment of immune checkpoint genes in the functional module but predicting a good prognosis by survival analysis. Among all the upregulated genes, FPR3, a G protein-coupled receptor essential for neutrophil activation, is the sole factor that predicts poor prognosis. GSEA analysis showed FRP3 upregulation synergizes with the activation of many pathways involved in carcinogenesis. Conclusions This study identified FPR3 as a key immune-related biomarker predicting a poor prognosis for breast cancer, revealing it as a promising targetable gene for immunotherapy.