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A Microplate Assay to Assess Chemical Effects on RBL-2H3 Mast Cell Degranulation: Effects of Triclosan without Use of an Organic Solvent
Published on: November 1, 2013
Unraveling the association between triclosan and breast cancer: A multidimensional research strategy integrating
Dongyang Wu1, Jiaquan Yuan2, Haoyang Xu2
1Guangxi University of Chinese Medicine, Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medic, Nanning 530020, Guangxi, China.
Objective:
The association between triclosan and breast cancer remains controversial, with early studies suggesting antitumor effects and recent evidence indicating pro-carcinogenic risks, but the key targets and molecular mechanisms remain unclear. This study integrated computational toxicology, network toxicology, machine learning, Mendelian randomization, and in vitro experiments to determine the direction of triclosan's effect on breast cancer and systematically elucidate its core molecular mechanisms.
Methods:
ProTox3 predicted carcinogenicity. Triclosan targets (SwissTargetPrediction/PharmMapper) were intersected with breast cancer DEGs (GSE42568/GSE70947) to build a PPI network. Three ML algorithms (RF, LASSO, SVM-RFE) with SHAP screened hub genes. Two-sample MR assessed causality; docking and 100 ns MD verified binding. MCF-7 cells were treated with triclosan to assess proliferation (CCK-8, EdU, Ki-67), colony formation, migration, cell cycle progression, and NR3C1 expression, with siRNA knockdown further confirming the mediation.
Results:
ProTox3 predicted moderate endocrine-related carcinogenicity. Intersection of 2,732 DEGs with triclosan targets yielded 98 candidates. Five hub genes (ADH5, PDK2, NR3C1, PTGS2, FABP4) were identified; RF AUC = 0.939. MR confirmed NR3C1 inversely causal on breast cancer risk (OR = 0.730, 95% CI:0.619-0.861, P < 0.001), and high NR3C1 predicted longer survival (HR = 0.86, 95% CI:0.77-0.95, P = 0.0042). MD showed stable binding (free energy: -116.676 ± 1.895 kJ/mol). In vitro, triclosan promoted proliferation (CCK-8/EdU, P < 0.01), colony formation/migration (P < 0.01), increased S-phase (P < 0.05), and reduced NR3C1 (P < 0.05); knockdown enhanced this, confirming downregulation.
Conclusion:
Triclosan stably binds and suppresses NR3C1, removing NR3C1-dependent restraint on proliferation, colony formation, migration, and cell cycle progression. NR3C1 negatively correlates with risk and is a favorable prognostic marker. This work provides a multi-level evidence chain from binding to prognosis, clarifying triclosan's pro-cancer mechanisms and offering clues for risk evaluation and intervention of endocrine-disrupting chemical-associated breast cancer.
Insights
Triclosan promotes breast cancer by suppressing the NR3C1 gene, which normally restrains cell growth. This study clarifies the pro-carcinogenic mechanisms of triclosan, an endocrine-disrupting chemical, and highlights NR3C1 as a potential prognostic marker.
Area of Science:
- Toxicology
- Genomics
- Computational Biology
Background:
- The role of triclosan in breast cancer is debated, with conflicting evidence on its effects.
- Key molecular targets and mechanisms underlying triclosan's influence on breast cancer are not well understood.
Purpose of the Study:
- To determine the effect of triclosan on breast cancer.
- To elucidate the core molecular mechanisms of triclosan's action in breast cancer using an integrated approach.
Main Methods:
- Integrated computational toxicology, network toxicology, machine learning, Mendelian randomization, and in vitro experiments.
- Utilized ProTox3 for carcinogenicity prediction, target identification, and protein-protein interaction network construction.
- Employed machine learning algorithms and Mendelian randomization to identify hub genes and assess causality, followed by molecular docking, molecular dynamics, and cell-based assays.
Main Results:
- Triclosan was predicted to have moderate endocrine-related carcinogenicity.
- Five hub genes, including NR3C1, were identified; NR3C1 showed an inverse causal relationship with breast cancer risk.
- In vitro studies demonstrated that triclosan promotes cell proliferation, colony formation, and migration by suppressing NR3C1 expression.
Conclusions:
- Triclosan promotes breast cancer by stably binding and suppressing NR3C1, thereby releasing the restraint on cell proliferation and migration.
- NR3C1 acts as a tumor suppressor, negatively correlating with breast cancer risk and serving as a favorable prognostic marker.
- This study provides comprehensive evidence clarifying triclosan's pro-cancer mechanisms and suggests implications for risk assessment and intervention strategies for endocrine-disrupting chemical-associated breast cancer.