Abstract
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.
Highlights
Fibroepithelial lesions (FELs) of the breast are a group of biphasic tumors that are highly heterogeneous in terms of their morphological as well as biological features
A strict false discovery rate (FDR) of 0.01 (1% cut off) was defined for identifying the confident peptide spectral matches where 7717 proteins were identified in the initial discovery phase with 6837 proteins quantified in at least two replicates shown in Supplementary Tables 2 and 3
Though there are several comprehensive genetic studies of phyllodes tumors (PTs), an unmet clinical need exists for accurate diagnosis, prognosis, and stratification of FELs, which could fundamentally improve the disease management strategies
Summary
Fibroepithelial lesions (FELs) of the breast are a group of biphasic tumors that are highly heterogeneous in terms of their morphological as well as biological features. FELs include well- defined fibroadenomas (FADs) and phyllodes tumors (PTs), with intersecting histologic attributes but varying clinical implications and outcomes [1, 2]. PTs are rare tumors and account for only < 1% of all breast neoplasms [4], and being highly aggressive requires wide local excision with negative margins. PTs are rapidly growing tumors that can often be misdiagnosed, leading to multiple diagnostic complications and invasive procedures [6]. Once these tumors become metastatic, the overall survival decreases to 30 months [7] and correlates with the increased risk of recurrence and rapid deterioration [8]. Molecular characterization of PTs is essential for careful evaluation and distinguishing between the different grades for better clinical outcome and management of this deadly disease
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