Abstract
Breast cancer (BC) is characterized by high heterogeneity regarding its biology and clinical characteristics. The Notch pathway regulates such processes as organ modeling and epithelial-to-mesenchymal transition (EMT).The aim of the study was to determine the effect of differential expression of Notch members on disease-free survival (DFS) in luminal type A (lumA) and triple negative (TN) BC.The differential expression of 19 Notch members was examined in a TCGA BC cohort. DFS analysis was performed using the log-rank test (p<0.05). Biological differences between DFS groups were determined with Gene Set Enrichment Analysis (GSEA) (tTest, FDR<0.25). Common expression profiles according to Notch signaling were examined using ExpressCluster (K-means, mean centered, Euclidean distance metric).The overexpression of HES1, LFNG and PSEN1 was found to be favorable for DFS in lumA, and lowered expression favorable for DFS in TN.GSEA analysis showed that differential Notch signaling is associated with cell cycle, tissue architecture and remodeling. Particularly, targets of E2F, early stage S phase transcription factor, were upregulated in the lumA unfavorable group and the TN favorable group differentiated on a basis of HES1 and PSEN1 expression.Summarizing, our analysis show significance of Notch signaling in BRCA progression through triggering EMT. Moreover, identification of numerous genes which overexpression is associated with disease recurrence may serve as a source of potential targets for a new anticancer therapy.
Highlights
Breast cancer (BC) is the most common tumor causing high mortality among women worldwide
Relatively high expression of HES1, Presenilin 1 (PSEN1) and LFNG was correlated with good prognosis in luminal type A (lumA) (HR=0.23, p=0.0064; hazard ratios (HRs)=0.24, p=0.0062; HR=0.28, p=0.029, respectively) (Figure 1), while lowered expression was associated with better disease-free survival (DFS) in triple negative immunophenotype (TN) (HR>100, p=0.0016; HR=11.22, p=0.033; HR=11.22, p=0.033, respectively) (Figure 2)
Gene Set Enrichment Analysis (GSEA) of chemical and genetic perturbations (CGPs) indicated the upregulation of gene sets associated with www.impactjournals.com/oncotarget resistance/sensitivity to various treatment and aberrant processes related to cancer progression/metastasis
Summary
Breast cancer (BC) is the most common tumor causing high mortality among women worldwide. The canonical Notch pathway is activated by interaction of DSL ligands with Notch receptors leading to two sequential proteolytic cleavages of the receptors: the first performed by ADAM/TACE metalloprotease, and the second in the remaining portion of Notch by the γ-secretase complex (comprising PSEN1, PSEN2, PEN2, APH1, nicastrin). This results in the release of the Notch intracellular domain (NICD), which in the nucleus forms a complex with DNA binding protein RPBJ and MAML family transcriptional coactivators. The latter induces the expression of Notch target genes encoding transcription factors (TFs), i.e. HES1 and HEY1 [8, 9]
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