Proteome profiling of serum reveals PSMD6 as a biomarker in breast cancer metastasis

Abstract

Abstract Breast cancer (BC) has the highest mortality rate and prevalence among cancers in females worldwide. Here, we performed proteomic profiling of 322 serum samples from the discovery cohort [56 healthy controls (HCs), 112 benign breast tumor (BBT) patients, and 154 BC patients] and a prospective validation cohort [27 HCs, 29 BBT patients and 57 BC patients]. Integrated proteomic analysis of tissue and serum samples revealed highly specific tumor biomarkers and demonstrated that the serum proteome can distinguish the different pathological substages in BC progression. We also identified PSMD6 as a potential metastatic breast cancer (MBC) biomarker. Comprehensive analysis of the multicenter independent validation cohort, which included retrospective and prospective cohorts including 61 HCs, 72 BBT patients, and 247 BC patients, indicated that PSMD6 overexpression was an important cause of BC metastasis and an indicator of poor prognosis. Further study revealed that the CLTA-PSMD6-neutrophil axis promotes the transition from invasive ductal carcinoma (IDC) to MBC. Importantly, CLTA amplification might be a potential therapeutic target for MBC patients. We also developed a highly accurate predictive model (accuracy = 0.87) to differentiate benign and malignant tumors and validated its good performance in the prospective validation cohort. Collectively, this study demonstrates the elaborate BC serum proteomic landscape and provides valuable information regarding serum biomarkers, which could reveal novel therapeutic targets and provide opportunities for MBC treatment.