Triple-negative breast cancer (TNBC) accounts for approximately 15% of all Breast Cancer (BC) cases with poorer prognosis and clinical outcomes compared to other BC subtypes due to greater tumor heterogeneity and few therapeutically targetable oncogenic drivers. To reveal actionable pathways for anti-cancer treatment, we use a proteomic approach to quantitatively compare the abundances of 6306 proteins across 55 formalin-fixed and paraffin-embedded (FFPE) TNBC tumors. We identified four major TNBC clusters by unsupervised clustering analysis of protein abundances. Analyses of clinicopathological characteristics revealed associations between the proteomic profiles and clinical phenotypes exhibited by each subtype. We validate the findings by inferring immune and stromal cell type composition from genome-wide DNA methylation profiles. Finally, quantitative proteomics on TNBC cell lines was conducted to identify in vitro models for each subtype. Collectively, our data provide subtype-specific insights into molecular drivers, clinicopathological phenotypes, tumor microenvironment (TME) compositions, and potential pharmacologic vulnerabilities for further investigations.
© 2025. The Author(s).