Proteomics characterization of triple-negative apocrine carcinoma reveals molecular features of progression and chemotherapy response

Triple-negative apocrine carcinoma (TNAC) is a rare and chemotherapy-insensitive subtype of triple-negative breast cancer (TNBC), characterized by specific morphology and molecular features. Despite limited chemotherapy response, TNAC shows favorable long-term survival, suggesting distinct resistance mechanisms. In this study, we present the first proteomics-based profiling of TNAC formalin-fixed paraffin-embedded (FFPE) samples using mass spectrometry. Our analysis reveals progressive activation of PI3K/AKT and androgen receptor (AR) signaling, along with upregulation of GTPase-related proteins, suggesting enhanced invasiveness. Post-chemotherapy TNAC displays increased inflammation and mixed ribosomal regulation, pointing to a metabolic shift in survival strategy. These findings support the rationale for exploring chemotherapy de-escalation strategies in TNAC, and highlight the potential utility of PI3K/AKT inhibitors and AR antagonists, possibly in combination with GTPase inhibitors, metabolic disruptors, or immunotherapy.