Circulating miRNAs (135a-5p, 646 AND 1271-5P) in breast cancer diagnosis and staging: integrative network and functional analysis

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Abstract
Introduction: Breast cancer (BC) remains a leading cause of cancer-related mortality among women worldwide.Despite advances in molecular diagnostics, reliable non-invasive biomarkers for early detection and disease staging remain limited. Circulating microRNAs (miRNAs) are promising epigenetic regulators involved in tumor development and progression.Methods: Determination of plasma miRNA (1271-5p, miR-646, and miR-135a-5p) differential expression profiles in an Egyptian cohort comprising 111 BC patients (stages 0–IV), 25 benign breast disease cases, and 24 healthy controls. Their diagnostic and stage-specific performance was assessed alongside integrative analyses of predicted and validated biological targets with network construction.Results: miR-1271-5p was downregulated in benign tumors but overexpressed across all BC stages. miR-646 was generally downregulated, with a notable increase in stage III, whereas miR-135a-5p was elevated in benign and early-stage disease before declining in metastatic stage IV. ROC analyses demonstrated strong discriminatory performance, with miR-1271-5p distinguishing early-stage BC from controls and benign lesions, miR-646 separating benign/early malignant cases from controls, and miR-135a-5p identifying metastatic disease. Combined miRNA panels improved discrimination between malignant and non-malignant samples and between early and advanced stages. Integrative analyses identified putative regulation of ZEB1, CCND2, FOXN3, and RUNX2, while TP53TG1, ZFAS1, XIST, and MALAT1 emerged as potential interaction hubs. Functional enrichment suggested involvement in AMPK, FOXO, SUMOylation, TP53-mediated, and immune-related pathways.Conclusions: Circulating miR-1271-5p, miR-646, and miR-135a-5p, individually and in combination, show promise as non-invasive diagnostic and stage-specific biomarkers for BC. Integrative network analyses provide insight into their putative roles in BC progression.

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