PLXNB2 promotes breast cancer progression and lung metastasis through the AMPK signaling pathway

Breast cancer is one of the most common malignancies among women worldwide, and metastasis remains the leading cause of breast cancer-related mortality. Although PLXNB2 regulates cell migration and intracellular signaling, its expression pattern and mechanistic role in breast cancer progression and lung metastasis remain unclear. This study investigated PLXNB2 expression in breast cancer (BRCA) and examined its contribution to tumor progression and pulmonary metastasis. PLXNB2 expression in tumor and adjacent normal tissues was analyzed using The Cancer Genome Atlas (TCGA) data. Weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, single-cell transcriptomics, and spatial transcriptomics were used to identify PLXNB2-associated pathways and cellular contexts. Associations with tumor grade and survival were evaluated in clinical cohorts, and the effects of lentiviral PLXNB2 knockdown on proliferation, migration, and invasion were assessed in breast cancer cell lines. Tumorigenicity and metastasis were further examined in vivo. PLXNB2 was significantly upregulated in breast cancer and was enriched predominantly in malignant epithelial cells. High PLXNB2 expression independently predicted poor overall survival in the GSE20711 cohort (HR = 1.610; 95% CI, 1.100-2.357; P = 0.013) and was positively associated with tumor grade (P < 0.05). WGCNA and transcriptomic analyses identified AMPK signaling as a key downstream pathway. PLXNB2 knockdown reduced p-AMPK and p-ACC1 levels without altering total AMPK or ACC1 expression, and reciprocal endogenous co-immunoprecipitation detected AMPK in PLXNB2 immunoprecipitates and PLXNB2 in AMPK immunoprecipitates, supporting an association between the two proteins. In vivo, PLXNB2 depletion reduced tumor growth, lung metastasis, and p-AMPK and p-ACC1 expression. These findings indicate that PLXNB2 promotes breast cancer progression and lung metastasis by activating AMPK signaling and may serve as a diagnostic, prognostic, and therapeutic biomarker.