The Notch ligand DLL1 exerts carcinogenic features in human breast cancer cells

Abstract

Breast cancer (BC) is the most common type of cancer in women and has a high rate of relapse and death. Notch signaling is crucial for normal breast development and homeostasis. Dysregulation of Notch receptors and ligands has been detected in different BC subtypes and shown to be implicated in tumor development, progression, drug resistance, and recurrence. However, the effects of Notch ligands in various types of BC remain poorly understood. In this study, we investigated the effects of the Notch ligand DLL1 in three different human BC cell lines: MCF-7, BT474, and MDA-MB-231. We showed that DLL1 expression is higher in MCF-7 and BT474 than in MDA-MB-231 cells, and that these cells respond differently to DLL1 downregulation. Functional assays in MCF-7 cells demonstrated that siRNA-mediated DLL1 downregulation reduced colony formation efficiency, migration, proliferation, caused cell cycle arrest at the G1 phase, and induced apoptosis. Gene expression studies revealed that these effects in MCF-7 cells were associated with increased expression of the cell cycle arrest p21 gene and decreased expression of genes that promote cell cycle progression (CDK2, SKP2), and survival (BCL2, BIRC5), unravelling possible mechanisms whereby DLL1 downregulation exerts some of its effects. Moreover, our results demonstrate that treatment with recombinant DLL1 increased MCF-7 cell proliferation and migration, confirming that DLL1 contributes to these processes in this BC cell line. DLL1 downregulation reduced the colony formation efficiency of BT474 cells and decreased the migration and invasion abilities of MDA-MB-231 cells but showed no effects in the proliferation and survival of these cells. Conclusions These findings provide further evidence that DLL1 exerts carcinogenic effects in BC cells. The dissimilar effects of DLL1 downregulation observed amongst MCF-7, BT474, and MDA-MB-231 cells is likely due to their distinctive genetic and biologic characteristics, suggesting that DLL1 contributes to BC through various mechanisms.

Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation

“…2f). DLL1 is a Notch ligand known to play a major role in cancers like breast cancer [47,48] and squamous neoplasias [49], and it is thought to be a promising therapeutic target [50]. Our ChIP-seq data showed CTCFL binding at the promoter of Dll1 and other CTAs such as TSP50 or Prss50 [51] and those belonging to the MAGE family (MAGE-B4, MAGE-E1, MAGE-F1) (Additional file 1: Figure S3A, B).…”

Serum levels of inflammation‐related markers and metabolites predict response to neoadjuvant chemotherapy with and without bevacizumab in breast cancers

“…In the chemotherapy-only arm, lower levels of four cytokines were associated with response (i.e., AXL, DLL1, sTNFR1 and CRP). Of these, four AXL has been associated with epithelial mesenchymal transition and resistance to therapy, 30,36 DLL1, a Notch ligand, promotes ER-positive 21 and ER-negative 37 breast cancer carcinogenesis, while sTNFR1 has been associated with the risk of breast cancer. 38 These results suggest that these known oncogenic molecules at the tumor site could be monitored systemically and still relate to response.…”

Notch Signalling in Breast Development and Cancer

“…Survivin prevents apoptosis through indirect and direct caspase inhibition ( Garg et al, 2016 ). Of the Bcl-2 family members, Notch upregulates the anti-apoptotic members including Bcl-2 and Bcl-X L , while downregulating pro-apoptotic members such as Bim and Noxa ( Portanova et al, 2013 ; Sales-Dias et al, 2019 ). Active Notch signalling reduces the sensitivity of TNBC cells to TRAIL-induced apoptosis ( Portanova et al, 2013 ).…”