TMEM70 drives breast cancer progression via mitochondrial oxidative phosphorylation and microenvironment remodeling

TMEM70 is a nuclear-encoded inner mitochondrial membrane protein involved in ATP synthase assembly and oxidative phosphorylation (OXPHOS). Although previous studies have linked TMEM70 to breast cancer prognosis and copy number alteration, its biological role in breast cancer remains incompletely defined. We integrated bulk transcriptomic, proteomic, clinical, spatial transcriptomic, and single-cell RNA-sequencing data to characterize TMEM70 expression, prognostic relevance, spatial distribution, immune context, intercellular communication, and pathway associations in breast cancer. Gain- and loss-of-function assays were performed to evaluate proliferation, migration, apoptosis, and mitochondrial function. Pharmacogenomic analysis, Connectivity Map screening, and molecular docking were used to identify candidate compounds associated with the TMEM70-high state. TMEM70 was consistently upregulated in breast cancer across datasets and platforms and was associated with poor prognosis. Spatial and single-cell analyses showed that TMEM70 was enriched in malignant regions and malignant cell populations. High TMEM70 expression was also associated with an immune-active but functionally constrained microenvironment, characterized by altered immune-cell correlations, cancer-immunity-cycle activity, immunoregulatory remodeling, and enhanced MIF-centered intercellular communication. Functionally, TMEM70 promoted proliferation and migration while suppressing apoptosis in breast cancer cells. Mechanistically, TMEM70 was closely associated with mitochondrial OXPHOS and maintained mitochondrial membrane potential, redox homeostasis, ATP production, and OXPHOS-related protein expression. Entinostat and clofibrate emerged as candidate compounds associated with the TMEM70-high program. TMEM70 is a clinically relevant pro-tumor factor in breast cancer and may promote malignant progression, at least in part, by sustaining mitochondrial OXPHOS and supporting a tumor-favoring microenvironment. TMEM70 may therefore serve as a promising biomarker and potential therapeutic target in breast cancer.