Paraben, extensively utilized as preservatives in cosmetics, pharmaceuticals, industrial products, and food due to its antimicrobial properties, represent pervasive environmental contaminants capable of bioaccumulation through dietary, dermal, and respiratory exposure, potentially leading to diseases including endocrine disruption, skin allergies, and breast cancer. As the endocrine-disrupting chemical (EDC) with estrogenic activity, paraben bind estrogen receptors (ERs), potentially disrupting hormonal homeostasis and increasing breast cancer risk. However, the molecular mechanisms linking paraben to breast carcinogenesis remain poorly defined. This study integrates network toxicology and molecular docking to systematically elucidate paraben-induced dysregulation in breast cancer pathogenesis. Paraben structures (2D/3D, SMILES) were retrieved from PubChem. Toxicological profiling employed ProTox and ADMETlab. Paraben-protein interactions were predicted via STITCH and SwissTargetPrediction, while breast cancer-associated targets were curated from GeneCards, OMIM, and TTD databases. The action targets of paraben were intersected with the breast cancer-related targets. Subsequently, the intersection targets were used to construct the compound regulatory network and perform PPI, GO, and KEGG analyses. The core targets of breast cancer caused by paraben were screened through Cytoscape. Finally, the relationship between the core targets and immune cell infiltration in breast cancer was explored, and molecular docking of paraben and the core targets was carried out. A total of 35 action targets of paraben were obtained from STITCH and SwissTargetPrediction. Meanwhile, 3,413 breast cancer-related targets were retrieved from GeneCards, OMIM, and TTD. After taking the intersection of these two sets of targets, 13 relevant targets were identified. PPI analysis revealed that proteins such as ESR1, ESR2, SERPINE1, and CA2 were located at the center of the network diagram and had close connections with other target proteins. Enrichment analysis demonstrated the molecular functions, biological processes involved, and related pathways of the intersection targets. Three core targets, namely ESR1, ESR2, and SERPINE1, were screened out using Cytoscape. Immune infiltration analysis indicated that in breast cancer, the expression of ESR1 was negatively correlated with the infiltration levels of CD8 + T cells and macrophages, while the expressions of ESR2 and SERPINE1 were positively correlated with the infiltration levels of CD8 + T cells and macrophages. Molecular docking showed that paraben had strong binding activities with ESR1, ESR2, and SERPINE1. Paraben exhibits estrogenic activity and may contribute to breast cancer development by targeting core molecules ESR1, ESR2, and SERPINE1, thereby regulating associated pathways that induce systemic immunosuppression or impede the recruitment of inflammatory responses.
Keywords: Breast cancer; Endocrine system; Estrogen; Network toxicology; Paraben.
© 2025. The Author(s).