Continuous TNF-α exposure in mammary epithelial cells promotes cancer phenotype acquisition via EGFR/TNFR2 activation

• Published in: Archives of pharmacal research Vol. 47; no. 5; pp. 465 - 480
• Main Authors: Lee, Jin-Hee, Hallis, Steffanus Pranoto, Kwak, Mi-Kyoung
• Format: Journal Article
• Language: English
• Published: Seoul Pharmaceutical Society of Korea 01.05.2024; 대한약학회
• Subjects: Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; ErbB Receptors - metabolism; Female; Humans; Mammary Glands, Human - drug effects; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; Medicine; NADPH Oxidase 4 - genetics; NADPH Oxidase 4 - metabolism; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Pharmacology/Toxicology; Pharmacy; Phenotype; Reactive Oxygen Species - metabolism; Receptors, Tumor Necrosis Factor, Type II - metabolism; Research Article; Signal Transduction - drug effects; Tumor Microenvironment; Tumor Necrosis Factor-alpha - metabolism; 약학; Tumor necrosis factor receptor 2; Tumor necrosis factor-alpha; Reactive oxygen species; Breast cancer; Epidermal growth factor receptor
• ISSN: 0253-6269; 1976-3786; 1976-3786
• DOI: 10.1007/s12272-024-01497-y

Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME.