Abstract
BACKGROUND: Breast cancer (BC) is the most common malignancy among women, with an increasing incidence correlated with age and diverse subtypes exhibiting distinct prognoses. The tumor microenvironment (TME) in BC is complicated. It is now believed that BC may acquire invasive characteristics and even extra proliferative ability from the TME through various mechanisms. However, most studies predominantly focus on the heterogeneity of tumor cells in BC, lacking a comprehensive depiction of intercellular communication within BC. Therefore, the present study aimed to elucidate cellular communication in the TME by integrated bioinformatic analysis of bulk mRNA and single-cell mRNA sequencing, combined with certain validation in clinical samples. METHODS: We first utilized single-cell sequencing data from GSE176078 to find out the most important cell communication pairs for the tumor microenvironment in BC then we conducted bulk-sequencing analysis to identify the differential expressed genes. Through correlation analysis, we sort out the top five most relevant genes to the most important cell communication pairs. We then validated the expression of the key genes of the aforementioned cell communication pairs and the five differentially expressed genes by qPCR on clinical samples. Furthermore, we analyzed the immunological relevance of these genes via a novel approach at single-cell resolution. RESULTS: The results of single-cell analysis indicated that the CXC12-CXCR4 ligand-receptor pair in the CXCL pathway and the FGF7-FGFR1 ligand-receptor pair in the FGF pathway are the most important cell communication pairs of the TME in BC. Subsequent bulk sequencing analysis showed that CHRDL1, SCARA5, LYVE1, PI16, and SAA2 were the most important differentially expressed genes linked to these cell communication pairs. In addition, we validated the expression of the key genes of the two cell communication pairs and the five genes in clinical samples, observing that the trends fitted the computational results. Finally, we studied the association of these genes with immune cell infiltration at single-cell level and had it cross-validated in bulk sequencing data, finding out that there were significant connections. CONCLUSION: In the tumor microenvironment of breast cancer, intercellular communication pairs of different cell types and molecules can exacerbate the development of breast cancer. among them, through the present study, we found that CXCL12-CXCR4 and FGF7-FGFR1 are the most important. Also, most significantly differentially expressed genes including CHRDL1, SCARA5, LYVE1, PI16, and SAA2 seemed to play a critical role in these mechanisms and immune cell infiltration, shaping the TME of BC.