Proteomic signatures in triple-negative breast cancer

An aggressive and heterogeneous malignancy, referred to as triple-negative breast cancer, is characterised by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Treatment options remain limited, relying primarily on chemotherapy due to the lack of well-defined therapeutic targets, which is linked with poor prognosis and high recurrence rates. Proteomics and other high-throughput technologies have significantly advanced TNBC research by enabling the identification of protein-based biomarkers with potential applications in diagnosis, prognosis, and treatment. Through protein biomarkers that affect immune checkpoints, cell-surface glycoproteins, and regulators of tumor microenvironment interactions, key protein signatures from tumor tissue, serum, and exosomal proteomics have been found to have the potential to predict chemotherapy response and disease progression. To develop new therapeutic approaches, these biomarkers are being investigated. Combining proteomics with other omics technologies, such as transcriptomics and genomics, enables the development of precision medicine approaches and provides deeper insights into the pathophysiology of TNBC. Clinically validated and newly developed protein biomarkers for diagnosis, prognosis, and treatment interventions are described in this review. The molecular mechanistic aspects have also been discussed. These biomarkers have the potential to aid in the classification, risk stratification, and development of personalized treatment approaches for TNBC. SIGNIFICANCE STATEMENT: Triple-negative breast cancer (TNBC) remains a highly aggressive and heterogeneous form of breast cancer, with very few treatment strategies. This review synthesizes past discoveries, current clinical applications, and future opportunities of proteomics in TNBC, making it highly relevant to the theme of this Special Issue on "Past, Present and Future of Proteomics." By consolidating evidence from human and other preclinical studies, it highlights how proteomic signatures have already transformed our understanding of TNBC biology and subtype classification, while also outlining their growing impact as diagnostic, prognostic, and therapeutic markers. Importantly, the review emphasizes the translational shift enabled by next-generation proteomic technologies to redefine precision medicine for TNBC. It showcases how proteomics can facilitate personalized medicine, drug repurposing, and rational combination therapies, and describes novel avenues such as single-cell proteomics and integrative immunoproteogenomics that are driving the field forward. Thus, this work not only consolidates what has been achieved but also provides perspectives on emerging technologies and innovative applications that could revolutionize biomarker discovery and clinical management of TNBC. It highlights proteomics as a critical pillar in shaping the future of cancer diagnostics and therapeutics, directly aligning with the scope and intent of the special issue.