Activated ERK Signaling Is One of the Major Hub Signals Related to the Acquisition of Radiotherapy-Resistant MDA-MB-231 Breast Cancer Cells

Abstract

Breast cancer is one of the major causes of deaths due to cancer, especially in women. The crucial barrier for breast cancer treatment is resistance to radiation therapy, one of the important local regional therapies. We previously established and characterized radio-resistant MDA-MB-231 breast cancer cells (RT-R-MDA-MB-231 cells) that harbor a high expression of cancer stem cells (CSCs) and the EMT phenotype. In this study, we performed antibody array analysis to identify the hub signaling mechanism for the radiation resistance of RT-R-MDA-MB-231 cells by comparing parental MDA-MB-231 (p-MDA-MB-231) and RT-R-MDA-MB-231 cells. Antibody array analysis unveiled that the MAPK1 protein was the most upregulated protein in RT-R-MDA-MB-231 cells compared to in p-MDA-MB-231 cells. The pathway enrichment analysis also revealed the presence of MAPK1 in almost all enriched pathways. Thus, we used an MEK/ERK inhibitor, PD98059, to block the MEK/ERK pathway and to identify the role of MAPK1 in the radio-resistance of RT-R-MDA-MB-231 cells. MEK/ERK inhibition induced cell death in both p-MDA-MB-231 and RT-R-MDA-MB-231 cells, but the death mechanism for each cell was different; p-MDA-MB-231 cells underwent apoptosis, showing cell shrinkage and PARP-1 cleavage, while RT-R-MDA-MB-231 cells underwent necroptosis, showing mitochondrial dissipation, nuclear swelling, and an increase in the expressions of CypA and AIF. In addition, MEK/ERK inhibition reversed the radio-resistance of RT-R-MDA-MB-231 cells and suppressed the increased expression of CSC markers (CD44 and OCT3/4) and the EMT phenotype (β-catenin and N-cadherin/E-cadherin). Taken together, this study suggests that activated ERK signaling is one of the major hub signals related to the radio-resistance of MDA-MB-231 breast cancer cells.

Mechanisms of Cell Adhesion Molecules in Endocrine-Related Cancers: A Concise Outlook

“…At the RNA level, overexpression of TPA diminished the expression of CDH1 and increased the expression of vimentin, fibronectin, and TGF-β1 ( 115 ). Circular RNA studies have shown that circNOLC1 ( 116 ) and circSCRIB ( 117 ) contribute to BC cell invasion and migration ability by reducing CDH1 and facilitating the tumorigenesis of breast cancer ( 118 ). Extracellular vesicles of insulin-like growth factor-1 (IGF-1), which is a crucial regulatory factor of mammary glands, promote the downregulation of CDH1 and upregulation of vimentin, N-cadherin, and MMP-9 in MDA-MB-231 breast cancer cells ( 119 ).…”

Function and Application of Flavonoids in the Breast Cancer

“…Most breast cancer patients receive radiotherapy after surgical resection; however, not all patients benefit equally because some have a locoregional relapse. The leading cause ( Table 2 ) of this relapse is radio resistance [ 63 ]. Radio-resistance is the adaptability of malignant cells or tissues to radiotherapy-induced damage and irradiation survival (IR) [ 64 , 65 ].…”

“…Radiation therapy can cause exhaustion and a red, sunburn-like rash where radiation is being delivered. Breast tissue may appear larger or stiffer as well [ 63 ]. These negative consequences might be debilitating.…”

Extracellular Vesicles and Cancer Stem Cells in Tumor Progression: New Therapeutic Perspectives

“…In regard to breast cancer, radioresistant MDA-MB-231 breast cancer cells (RT-R-MDA-MB-231 cells) are malignant cells with a high metastatic activity, proliferation rate, and expression of CSC and EMT markers [ 99 ]. Paramanantham et al hypothesized the presence of an altered signal in those cells and set up an antibody array analysis on both radioresistant MDA-MB-231 and parental ones (p-MDA-MB-231) [ 100 ]. They found an upregulation of MAPK1, dual specificity protein kinase (CLK1), and fibroblast growth factor 22 (FGF22) and a downregulation of caspase-3 in RT-R-MDA-MB-231 cells.…”

“…Molecular analysis revealed that ERK inhibition induced the cleavage of poly(ADP-ribose) polymerase 1 (PARP-1) and caspase-3 (apoptosis markers) in p-MDA-MB-231 cells and the activation of the apoptosis-inducing factor (AIF), which positively regulates cyclophilin A (CypA) protein (biomarker of necroptosis), in RT-R-MDA-MB-231 cells. In the latter, ERK inhibition markedly suppressed CSC and EMT markers [ 100 ]. Therefore, ERK signaling is strongly involved in the radioresistance of MDA-MB-231 breast cancer cells, suggesting that its targeting may offer a potential therapeutic strategy.…”