Common profiles of Notch signaling differentiate disease-free survival in luminal type A and triple negative breast cancer

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.

Upregulation of HES1 Promotes Cell Proliferation and Invasion in Breast Cancer as a Prognosis Marker and Therapy Target via the AKT Pathway and EMT Process

“…Meanwhile, HES1 upregulation was correlated with lower PFS and OS in patients with TNBC. A recent study also revealed that HES1 upregulation predicts an unfavourable prognosis in TNBC 29 . To date, there is still no targeted and effective treatment strategy for TNBC due to deficiencies in therapeutic targets.…”

Significance of intrinsic breast cancer subtypes on the long-term prognosis after neoadjuvant chemotherapy

“…Additionally, PRS was significantly better for patients with luminal breast cancer who achieved pCR, but not for those with TNBC. Luminal breast cancer comprises epithelial cells and has low invasion capability, whereas TNBC comprises mesenchymal cells, and has high invasion and migration capabilities [ 28 , 29 ]. Compared to that of the primary tumor, relapsed breast cancer after NAC and surgery often acquires resistance to chemotherapy; thus, the prognosis may depend on the degree of invasion or migration rather than immunoactivity.…”

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

“…A previous study found that PSEN1 was involved in the process of invasion and metastasis of gastric cancer both in vitro and vivo, 30 which may be regarded as a potential biomarker and therapeutic target. On the other hand, PSEN1 was also reported to be a tumour suppressor, and the enhanced expression of PSEN1 was associated with a favourable disease‐free survival for patients with breast cancer32 and skin cancer 33. However, little is known for its role in ovarian cancer.…”