Genome-wide association and functional investigation of M2-like tumor-associated macrophages identified hub genes for breast cancer

M2-like tumor-associated macrophages (M2-like TAMs) have great potential in promoting oncogenesis and provide the potential biomarkers for diagnosis and treatment of tumor. However, the role of M2-like TAMs in breast invasive carcinoma (BRCA) is still unclear. Based on The Cancer Genome Atlas of America (TCGA) and the Gene Expression Omnibus (GEO) databases, we compared multiple tumors and found the diametrically opposite survival of M1-like and M2-like macrophages in BRCA. And then, we systematically explored the function of M2-like TAMs in BRCA using differentially expressed analysis, weighted gene co-expression network analysis (WGCNA), GO and KEGG analysis, Nomogram, Gene Set Enrichment Analysis (GSEA), CIBERSORT algorithm, pan-cancer and mendelian randomization study. We evaluated the sensitivity and resistance to drugs targeting hub genes using the Genomics of Drug Sensitivity in Cancer (GDSC) database. A total of 85 M2-like TAM-related genes were screened out and the results of functional enrichment analysis were correlated with tight junction, Rap1 signaling pathway and PI3K-Akt signaling pathway. FOXA1 , ERBB3 , MUC1 , AGR2 were identified as hub genes by protein interaction (PPI) network, "CytoNCA" toolkit and degree algorithm. Additionally, nomogram and ROC curve indicated great prognostic performance, and the high expressing four hub genes were positively correlated with M2-like macrophages. FOXA1 and ERBB3 expressed at higher levels in BRCA than in other tumors by pan-cancer analysis. In fixed effected inverse variance weighting, we found that FOXA1 , ERBB3 , MUC1 were positively associated with BRCA risk. Finally, highly FOXA1 , ERBB3 , MUC1 expressing patients were more sensitive to Lapatinib through drug sensitivity analysis. Our studies contribute to understand the M2-like TAM-related mechanisms involved in breast cancer, which provide further insights into drug sensitivity therapy.