HCCS Serves as Potential Prognostic Biomarker and Therapeutic Target in Human Breast Cancer

Breast cancer is a leading cause of cancer-related morbidity and mortality in women worldwide. Among its subtypes, triple-negative breast cancer (TNBC) poses the greatest therapeutic challenge due to its aggressive nature and lack of targeted treatments. Holocytochrome c synthase (HCCS), a mitochondrial enzyme essential for cytochrome c maturation, may play a pivotal role in cancer pathogenesis.

This study aimed to investigate the expression profile, epigenetic regulation, immune interactions, prognostic significance, and molecular networks of HCCS across cancers, with a particular focus on breast cancer and its subtypes.

Publicly available datasets and bioinformatics tools were employed to analyze HCCS expression, methylation, survival outcomes, immune infiltration, and interaction networks. Expression and clinical outcomes were examined using TCGA, while methylation and expression patterns were assessed via UALCAN and TNMplot. Survival analyses were performed using Kaplan-Meier Plotter, and immune infiltration was evaluated with TIMER2.0. Protein-protein interaction networks were generated with STRING, and functional enrichment was conducted through g:Profiler. Key findings were validated in independent breast cancer cohorts from GEO and the GOBO platform.

HCCS was significantly overexpressed in multiple cancers, with the highest upregulation observed in breast cancer, particularly TNBC. Hypomethylation of the HCCS promoter was associated with increased expression. High HCCS expression correlated with poorer relapse-free survival and greater immune infiltration, including CD4⁺ T cells, CD8⁺ T cells, macrophages (M1/M2), mast cells, and regulatory T cells. Protein-protein interaction analysis revealed HCCS-associated genes enriched in mitochondrial and apoptotic pathways. Validation across independent datasets consistently supported the association of elevated HCCS expression with poor prognosis in breast cancer.

This integrated bioinformatics analysis highlights HCCS as a potential prognostic biomarker and therapeutic target in breast cancer, particularly in TNBC, although further experimental validation is required before clinical application.