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.ConclusionsThese 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.
Highlights
Breast cancer is the most common cancer in women worldwide, and besides being the second leading cause of death by this malignancy, it accounts for nearly 30% of new cancer diagnosis [1]
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 Breast cancer (BC) through various mechanisms
To investigate the functional role of DLL1 in these BC cells, MCF-7, BT474, and MDAMB-231 cells were transfected with two DLL1 specific siRNAs (DLL1-siRNA1 and DLL1siRNA2), to downregulate DLL1 expression, and with a non-targeting siRNA (Ctr), as a negative control. siRNA-mediated DLL1 downregulation was confirmed by quantitative real-time RT-PCR (qRT-PCR) and immunoblotting
Summary
Breast cancer is the most common cancer in women worldwide, and besides being the second leading cause of death by this malignancy, it accounts for nearly 30% of new cancer diagnosis [1]. BC is a highly heterogeneous disease that can be classified into various types based on pathology, tumor grade and stage, and gene expression profile. According to the gene expression signature BC can be divided into 4 subtypes: luminal A and luminal B (positive for the oestrogen and progesterone receptors (ER+ and PR+)), HER2+ (human epidermal growth factor receptor), and triple-negative breast cancers (TNBC) [2]. Triple-negative breast cancers include a heterogeneous subgroup of tumors that lack expression of the ER and PR hormone receptors, as well as of the HER2 protein, and exhibits the most aggressive phenotype and a poor clinical outcome [2]. Despite early detection and targeted therapy, tumor recurrence and metastasis are the main cause of death in BC patients [1]. Understanding the mechanisms implicated in BC is crucial for the design of more effective and targeted therapies
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