Molecular mechanism of bisphenols induction of breast cancer through PGR revealed by network toxicology and
Baowen Yuan1, Yu Li1, Jinyuan Chang2
1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Bisphenols are widely found in plastic products and may be hazardous to human health due to their estrogenic effects. Bisphenols may be involved in the carcinogenic process through endocrine-disrupting properties, especially in breast cancer. However, the specific targets and mechanisms of bisphenols remain unclear. By integrating network toxicology, transcriptomics, and molecular docking technology, this study aims to methodically identify the possible targets and mechanisms of five bisphenols in causing breast cancer. Targets linked to breast cancer were screened using the disease database, and bisphenols targets were screened using the compound and its prediction database. Ultimately, 424 targets associated with bisphenols and breast cancer were selected. With the STRING database, Cytoscape, and enrichment analysis, 12 core targets were identified, which are predominantly engaged in chemical carcinogenesis - receptor activation and estrogen signaling pathway. Furthermore, 26 common differentially expressed genes, including the core target PGR, were found by transcriptomic analysis in human breast cancer cells exposed to four bisphenols. Molecular docking showed that the PGR protein and five bisphenols had the lowest binding energy (-7.7 ∼ -7.0 kcal/mol) and the highest binding affinity. This study suggests that bisphenols may bind to PGR and induce its expression, thus contributing to breast carcinogenesis. This may happen via chemical cancer-receptor activation, estrogen signaling pathway, and endocrine resistance pathway. This study offers a theoretical basis for disease prevention and control besides providing a new perspective on the pathogenic mechanism of environmental pollutants. It also promotes the application of the integrated research strategy of network toxicology, bioinformatics, and molecular docking technology in environmental pollutants research.
Insights
Bisphenols, common in plastics, may cause breast cancer by affecting the progesterone receptor (PGR). This research reveals potential endocrine-disrupting mechanisms for environmental pollutants.
Area of Science:
- Environmental toxicology
- Molecular biology
- Cancer research
Background:
- Bisphenols are endocrine-disrupting chemicals found in plastics with potential estrogenic effects.
- Their role in breast cancer development and specific molecular mechanisms remain largely unknown.
- Understanding these mechanisms is crucial for public health and environmental safety.
Purpose of the Study:
- To identify the molecular targets and mechanisms through which five bisphenols contribute to breast cancer.
- To investigate the role of bisphenols in chemical carcinogenesis, receptor activation, and estrogen signaling pathways.
- To explore the potential link between bisphenols, progesterone receptor (PGR), and breast cancer development.
Main Methods:
- Integrated network toxicology, transcriptomics, and molecular docking.
- Screened bisphenol and breast cancer-related targets using disease and compound databases.
- Utilized STRING database, Cytoscape, and enrichment analysis to identify core targets.
- Performed transcriptomic analysis on human breast cancer cells exposed to bisphenols.
- Conducted molecular docking to assess binding affinity between bisphenols and identified targets.
Main Results:
- Identified 424 targets associated with bisphenols and breast cancer.
- Discovered 12 core targets primarily involved in chemical carcinogenesis, receptor activation, and estrogen signaling.
- Found 26 common differentially expressed genes, including the core target PGR, in bisphenol-exposed breast cancer cells.
- Molecular docking revealed strong binding affinity between five bisphenols and the PGR protein.
Conclusions:
- Bisphenols may contribute to breast carcinogenesis by binding to and inducing the expression of the progesterone receptor (PGR).
- The proposed mechanisms involve chemical cancer-receptor activation, estrogen signaling, and endocrine resistance pathways.
- This study provides a theoretical basis for disease prevention and offers a new perspective on the pathogenic mechanisms of environmental pollutants.
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