Coordinated DNA methyltransferase 3A and methyltransferase-like 7A activity reprograms the tumor microenvironment through discoidin domain receptor 1 signaling.

OBJECTIVE: Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival. Regulatory T cells (Tregs) in the tumor microenvironment (TME) promote immune evasion and metastasis, increasing recurrence risk. This study determined how the epigenetic regulators, DNMT3A and METTL7A, modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis. METHODS: RNA sequencing (RNA-seq) was used to identify differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Machine learning algorithms, including least absolute shrinkage and selection operator (LASSO), supported vector machine-recursive feature elimination (SVM-RFE) and ElasticNet identified DDR1 as a key gene. Validation included RT-qPCR, western blot, MSP, MeRIP-qPCR, and Co-IP to assess epigenetic regulation. Functional assays (CCK-8, Transwell, and Treg differentiation/chemotaxis) and xenograft models evaluated the role of DDR1 in tumor progression and recurrence. RESULTS: DNMT3A upregulated DDR1 via DNA methylation, while METTL7A enhanced DDR1 mRNA stability via m6A modification. Co-regulation activated the DDR1/STAT3/CXCL5 axis, which boosted cancer cell proliferation, migration, and invasion. CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo. DDR1 silencing reversed these effects, confirming that DDR1 has a pivotal role in breast cancer recurrence. CONCLUSIONS: DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation, which drives Treg-mediated immune suppression and recurrence. This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.