HDHD5 promotes triple-negative breast cancer growth and drives EMT-associated phenotypes via regulating S100A4

Abstract Purpose Triple-negative breast cancer (TNBC) displays an aggressive clinicopathological profile. Despite cytotoxic chemotherapy being the primary systemic therapy, complete responses are achieved in fewer than 30% of patients, highlighting the need for new therapeutic targets and a deeper understanding of disease-driving mechanisms. Methods This study identified key oncogenic factors in TNBC through multi-omics differential analyses. Cell proliferation, migration, and invasion abilities were assessed using CCK-8, colony formation, and transwell migration and invasion assays. Quantitative proteomics was applied to profile downstream protein alterations following HDHD5 knockdown. Western blotting and RT-qPCR were used to examine expression levels in different samples. Xenograft tumor model was employed to investigate the in vivo functions of HDHD5. Results HDHD5 was highly expressed in TNBC and its elevated expression was associated with poor patient prognosis. Functional studies demonstrated that HDHD5 promotes TNBC cell proliferation and colony formation, as well as enhances cell migration and invasion. Mechanistically, HDHD5 facilitates epithelial–mesenchymal transition (EMT) associated phenotypes and promotes migratory and invasive capacities in TNBC cell lines, at least in part, through regulation of S100A4. Consistently, HDHD5 promoted TNBC tumor growth both in vitro and in vivo via S100A4. Conclusion Our study reveals HDHD5 as a previously unrecognized driver of tumor progression in TNBC and highlights its potential as a therapeutic target and prognostic biomarker for this aggressive breast cancer subtype.