Proteomics Landscape of Triple-Negative Apocrine Breast Carcinoma Reveals Molecular Mechanisms of Tumorigenesis and Characteristics of Chemo-insensitivity

Triple-negative apocrine breast carcinoma (TNAC) is a rare type of triple-negative breast cancer (TNBC) characterized by apocrine morphology. Due to its low clinical incidence, TNAC has not been well studied at the molecular level in terms of cellular mechanisms of tumorigenesis and treatment response. In this study, we collected formalin-fixed paraffin-embedded samples from 31 patients diagnosed with invasive TNAC. Mass spectrometry analysis and whole-exome sequencing were performed to systematically construct the proteome and mutation landscape of the TNAC. Comparing ductal carcinoma in situ (DCIS), invasive, and adjacent normal tissues, we observed increased cadherin binding and ligase activity during tumorigenesis, heightened extracellular matrix signaling at tumor initiation, and elevated GTPase activity during tumor progression. Besides, we discovered genes such as C3 and COL18A1 enriched in somatic mutations are also significantly dysregulated in invasive TNAC. Additionally, by assessing biopsies before neo-adjacent chemotherapy, we provided molecular evidence supporting clinical observations of chemotherapy insensitivity in TNAC patients. We further identified a protein panel (CAPN1, CORO1B, HK1, RAP1B, and VPS4B) differentiating TNAC from non-apocrine TNBC, which could potentially serve as diagnostic markers. Taken together, this study represents the first large-scale proteomics analysis of TNAC and may provide guidance on decisions regarding the chemotherapy treatment of TNAC patients.