Gene Expression Profiling of Fibroepithelial Lesions of the Breast

Abstract

Fibroepithelial lesions of the breast (FELs) are a heterogeneous group of neoplasms exhibiting a histologic spectrum ranging from fibroadenomas (FAs) to malignant phyllodes tumors (PTs). Despite published histologic criteria for their classification, it is common for such lesions to exhibit overlapping features, leading to subjective interpretation and interobserver disagreements in histologic diagnosis. Therefore, there is a need for a more objective diagnostic modality to aid in the accurate classification of these lesions and to guide appropriate clinical management. In this study, the expression of 750 tumor-related genes was measured in a cohort of 34 FELs (5 FAs, 9 cellular FAs, 9 benign PTs, 7 borderline PTs, and 4 malignant PTs). Differentially expressed gene analysis, gene set analysis, pathway analysis, and cell type analysis were performed. Genes involved in matrix remodeling and metastasis (e.g., MMP9, SPP1, COL11A1), angiogenesis (VEGFA, ITGAV, NFIL3, FDFR1, CCND2), hypoxia (ENO1, HK1, CYBB, HK2), metabolic stress (e.g., UBE2C, CDKN2A, FBP1), cell proliferation (e.g., CENPF, CCNB1), and the PI3K-Akt pathway (e.g., ITGB3, NRAS) were highly expressed in malignant PTs and less expressed in borderline PTs, benign PTs, cellular FAs, and FAs. The overall gene expression profiles of benign PTs, cellular FAs, and FAs were very similar. Although a slight difference was observed between borderline and benign PTs, a higher degree of difference was observed between borderline and malignant PTs. Additionally, the macrophage cell abundance scores and CCL5 were significantly higher in malignant PTs compared with all other groups. Our results suggest that the gene-expression-profiling-based approach could lead to further stratification of FELs and may provide clinically useful biological and pathophysiological information to improve the existing histologic diagnostic algorithm.

Integrating single‐cell and spatial transcriptomes reveals COL4A1/2 facilitates the spatial organisation of stromal cells differentiation in breast phyllodes tumours

“…Stroma tB in P2 shared signature genes with Stroma tC, including RGS5 , ITGA1 , NR2F2 , COL4A1/2 , THY1 , IGFBP7 , PDGFRB , NOTCH3 and ANGPT2 . A recent study demonstrated that the PI3K–Akt and MAPK pathways were upregulated in malignant breast PTs 32 ; here, our scRNA‐seq data showed that these pathways displayed heterogeneous enrichment in stromal cells (Figure S3 ).…”

CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway

“…Interestingly, the PI3K‐AKT signaling pathway was investigated in both scRNA‐seq in PT tissues (Figure 3A ) and mRNA sequencing in cell lines (Figure 3C ). Previous reports suggested that activation of the AKT pathway may be associated with malignant transformation and recurrence of PT [ 18 , 19 ]. To confirm these sequencing results, the pathway was detected by WB, revealing that the PI3K‐AKT pathway was activated in malignant PT cells compared to benign PT cells (Figure 3D ).…”

“…Prior studies have identified CD146 as a marker of vascular endothelial cells. It has also been found that AA98 can inhibit angiogenesis [ 19 ]. Interestingly, in the AA98 application group, the size of 2 PDX tumors (from Donor 1 with lower level of CD146 compared to Donor 2 and 3) was larger than the size of 4 other PDX tumors (from Donor 2 and 3).…”

A Comprehensive Review of Breast Fibroadenoma: Correlating Clinical and Pathological Findings

“…Identifying specific genetic alterations associated with these lesions may provide additional tools for confirming their benign nature and distinguishing them from other breast conditions, including malignant tumors. This could enhance our ability to make precise diagnoses and guide appropriate clinical management [ 17 ].…”