Decoding the Tumor-Suppressive Landscape of Scavenger Receptor Class A Member 5: A Network-Based Analysis Linking Lipid Metabolism and Immuno Regulation in Breast Cancer

ABSTRACT Background The tumor microenvironment (TME) significantly impacts breast cancer progression, with stromal and immune components influencing tumor behavior. The scavenger receptor SCARA5 is recognized as a tumor suppressor in various cancers, but its role in breast cancer remains uncertain. Methods We performed integrative transcriptomic analyses of bulk RNA-seq data from TCGA-BRCA, validated with GTEx, to investigate SCARA5 expression and its clinical significance. Differential expression, PAM50 subtype classification, PCA/t-SNE clustering, and ROC analyses were used to assess diagnostic potential. Functional enrichment (GO, KEGG, Reactome), PPI networks, and co-expression analyses explored pathways related to SCARA5. Single-cell transcriptomic datasets (TISCH2, Broad Portal) and spatial profiling (Human Protein Atlas) were employed to examine cellular and spatial localization. The prognostic importance was assessed using GEPIA2 survival analysis. Results SCARA5 was significantly downregulated in breast tumors, especially in Her2-enriched and Luminal B subtypes, with ROC curves confirming its diagnostic importance. Enrichment and PPI analyses linked SCARA5 to lipid metabolism, immune regulation, and scavenger receptor pathways. Co-expression studies showed associations with lipid metabolism genes (FABP4, ADIPOQ, CD36) and immune-related genes (CLEC3B, LYVE1). Single-cell data indicated SCARA5 expression was limited to fibroblasts, endothelial cells, and immune subsets, with rare expression in malignant epithelial cells. Spatial analysis confirmed stromal enrichment, mainly in areas rich in fibroblasts and endothelial cells. Survival analysis demonstrated worse outcomes in patients with HER2+ and Luminal B breast cancers who had low SCARA5 expression. Conclusion SCARA5 is a stromal-enriched gene with potential tumor-suppressive and immunometabolic regulatory roles in breast cancer. Its diagnostic and prognostic significance, especially in aggressive subtypes, highlights its potential as a biomarker and therapeutic target within the tumor stroma.