Bcl-2 binding component 3 (BBC3) as a precision biomarker in breast cancer

Breast cancer is the most prevalent carcinoma in women globally, and the identification of sensitive and specific serum biomarkers is important for its early detection, monitoring, and prognosis. Bcl-2 binding component 3 (BBC3), also known as p53 upregulated modulator of apoptosis (PUMA), is a proapoptotic- BH3-only protein whose dysregulated expression in tumor tissues and circulation implicates it as a potential diagnostic biomarker. However, the analytical performance, preanalytical- requirements, and clinical utility of serum BBC3 quantification have not been rigorously assessed according to clinical chemistry- standards. This review examines the molecular regulation and structural features of BBC3 relevant to analytical assay design, key preanalytical- variables, including specimen collection, processing intervals, and storage conditions, and evaluates quantitative platforms, such as enzyme-linked immunosorbent assay (ELISA), quantitative reverse-transcription polymerase chain reaction (qRT-PCR), digital polymerase chain reaction (digital PCR), and mass spectrometry (MS)- in terms of limits of detection, quantification, precision, accuracy, linearity, and specificity. We reviewed clinical validation data from multiple cohorts and reported the sensitivity, specificity, receiver operating characteristic area under the curve (ROC-AUC), predictive values, and correlations with tumor stage and treatment response. Comparative analyses with established markers, including cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA), cell-free DNA (cfDNA), and microRNA (miRNA) panels are presented. Additionally, operational recommendations are provided for quality control procedures, establishment of reference intervals, throughput optimization, and integration with automated platforms. The primary contribution of this study lies in its comprehensive review of molecular insights, assay validation, and clinical application strategies specifically designed to meet the requirements of clinical laboratories. This study aimed to provide laboratory scientists and clinicians with a standardized protocol for adopting serum BBC3 measurements in routine practice, thereby enhancing early detection, therapeutic monitoring, and individualized patient management in patients with breast cancer.