Quantitative proteome profiling stratifies fibroepithelial lesions of the breast.

Breast fibroepithelial lesions (FELs) include heterogeneous pathological tumors, involving indolent fibroadenoma (FAD) to potentially aggressive phyllodes tumors (PTs). The current grading system remains unreliable in differentiating these tumors due to histological heterogeneity and lack of appropriate markers to monitor the sudden and unpredictable malignant transformation of PTs. Thus, there exists an imminent need for a marker-based diagnostic approach to augment the conventional histological platform that could lead to accurate diagnosis and distinction of FELs. The high- throughput quantitative proteomic analysis suggested that FAD and PTs form distinct clusters away from borderline and malignant though there exist marked differences between them. Interestingly, over-expression of extracellular matrices (ECM) related proteins and epithelial-mesenchymal transition (EMT) markers in borderline PTs led us to hypothesize a model of deposition and degradation leading to ECM remodeling and EMT acquisition triggering its malignant transformation. We also identified three candidate biomarkers such as MUCL1, HTRA1, and VEGDF uniquely expressed in FAD, borderline, and malignant PTs, respectively, which were further validated using immunohistochemistry. The present work shed light on a brief mechanistic framework of PTs aggressive nature and present potential biomarkers to differentiate overlapping FELs that would be of practical utility in augmenting existing diagnosis and disease management for this rare tumor.