Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with high malignancy, rapid progression, and a poor 5-year survival rate of ~77%. Due to the lack of targeted therapies, treatment options are limited, highlighting the urgent need for novel therapeutic strategies. Myoepithelial cells (MECs) in the tumor microenvironment may significantly influence TNBC development and progression. Methods: This study used single-cell RNA sequencing to compare the MEC gene expression in the normal versus TNBC tissues. TNBC-associated MECs showed increased expression of proliferation- and immune-related genes (e.g., FDCSP, KRT14, and KRT17) and decreased expression of inflammatory and extracellular matrix-related genes (e.g., CXCL8, SRGN, and DCN). Copy number variation and pseudotime analyses revealed genomic alterations and phenotypic dynamics in MECs. A CoxBoost-based prognostic model was developed and validated across 20 survival cohorts, integrating immune profiling, pathway enrichment, and drug sensitivity analyses. Mendelian randomization identified TPD52 as a TNBC risk-associated gene. siRNA knockdown of TPD52 was performed in TNBC cell lines to evaluate its effects on proliferation and migration. Results: TNBC MECs displayed significant changes in the gene expression and genomic integrity, impacting immune responses and tumor invasion. The prognostic model effectively predicted 1-, 3-, and 5-year survival outcomes, stratifying high-risk patients with enriched cell cycle and DNA replication pathways, reduced immune checkpoint expression, and chemotherapy resistance. TPD52 was identified as a tumor-promoting gene, and its knockdown suppressed TNBC cell proliferation and migration. Conclusion: This study highlights MECs' role in TNBC progression, provides a CoxBoost prognostic model for personalized treatment, and identifies TPD52 as a potential therapeutic target for TNBC intervention.