Multi-omics Data Reveal SLC9A3R2 Promotes Breast Cancer Progression and an Immunosuppressive Microenvironment

The molecular mechanisms driving the occurrence and progression of breast cancer remain unclear, necessitating the identification of novel molecular biomarkers and therapeutic targets. This study aims to investigate the role of SLC9A3R2 (NHERF2) in breast cancer progression via an integrated multi-scale approach. Analysis of The Cancer Genome Atlas (TCGA) data revealed that SLC9A3R2 is upregulated at both protein and mRNA level in breast cancer tissues, related to advanced tumor stage and poor prognosis, especially in luminal subtypes. Functional enrichment analyses linked high SLC9A3R2 expression to epithelial-mesenchymal transition (EMT), estrogen response, and PI3K-AKT/MAPK signaling pathways. Additionally, SLC9A3R2 expression was negatively correlated with the infiltration level of CD8+ T cell as well as the expression of four main immune checkpoint molecules. Single-cell RNA sequencing analysis of patient samples revealed that SLC9A3R2-positive tumor epithelial cells mediate aberrant cellular communication with endothelial cells, fibroblasts, and macrophages via specific ligand-receptor pairs involving FN1, COL1A1, and COL1A2. Cell functional assays showed that knockdown of SLC9A3R2 significantly impaired the proliferation, migration, and invasion capacities of breast cancer cells. Our findings establish SLC9A3R2 as a key promoter of breast cancer progression, influencing both intrinsic oncogenic pathways and the extrinsic tumor microenvironment (TME), which provides a novel insight for breast cancer treatment.