SIGLEC15 modulates the immunosuppressive microenvironment and suppresses malignant phenotypes in triple-negative breast cancer

Previous studies have demonstrated a significant association between sialic acid binding Ig-like lectin 15 (<i>SIGLEC15)</i> and both the progression of malignant tumors and immune infiltration. This study comprehensively analyzed and elaborated the function and related mechanism of <i>SIGLEC15</i> in breast cancer. We analyzed <i>SIGLEC15</i> expression levels and predicted its functions using mRNA sequencing in a population-based dataset. Single-cell RNA sequencing was utilized to investigate the biological roles of <i>SIGLEC15</i> within the tumor microenvironment (TME). Finally, we conducted both <i>in vivo</i> and <i>in vitro</i> experiments to validate the findings derived from the RNA sequencing analyses. Elevated <i>SIGLEC15</i> expression was associated with favorable outcomes in breast cancer patients. Tumor cells exhibiting high <i>SIGLEC15</i> expression demonstrated reduced epithelial-mesenchymal transition (EMT) tendencies compared to those with lower expression levels, potentially through the regulation of <i>ZEB1</i> expression. However, anti-tumor immunity was significantly suppressed in the TME containing these tumor cells. Analysis of protein expression in patient samples revealed a negative correlation between <i>SIGLEC15</i> expression and CD4, CD8 T-cell infiltration. In mouse models, tumor cells overexpressing <i>SIGLEC15</i> exhibited diminished invasive and migratory capabilities. Furthermore, both <i>in vitro</i> and <i>in vivo</i> experiments confirmed that Nutlin-3a has a more pronounced inhibitory effect on breast cancer cells with elevated <i>SIGLEC15</i> expression. The expression level of SIGLEC15 can serve as a biomarker to assess the malignancy of breast cancer and the degree of immune infiltration. Monitoring SIGLEC15 expression levels can facilitate more informed and personalized clinical decision-making for the treatment of breast cancer patients.