Estrogen-related mechanisms underlying bisphenol A-Induced proliferation and migration in MCF-7 breast cancer cells: An integrated network toxicology, molecular docking, and in vitro study.

Bisphenol A (BPA) is an environmental endocrine-disrupting chemical widely present in plastics and food packaging. Owing to its estrogen-like activity, BPA may increase the risk of estrogen-related tumors, including breast cancer, by interfering with endocrine function; however, the underlying molecular mechanisms remain unclear. To systematically evaluate the potential effects of BPA on estrogen-related tumors, including breast, ovarian, and endometrial cancers, this study integrated network toxicology, molecular docking, and in vitro validation. Bioinformatics approaches were first used to predict the potential targets of BPA in these tumors, followed by functional validation using an MCF-7 breast cancer cell model. Through multi-database target screening, a "BPA-target-disease" interaction network was constructed. Functional enrichment analysis showed that BPA-related targets were significantly enriched in biological processes associated with cell-cycle regulation, estrogen receptor signaling, and cell migration and invasion. Molecular docking analysis was subsequently performed using experimentally resolved crystal structures of ESR1, CCNA2, EPHA2, CDK1, and CDK2 obtained from the RCSB Protein Data Bank, demonstrating favorable binding of BPA to these key proteins. Based on these network predictions, in vitro functional validation was subsequently performed in MCF-7 breast cancer cells. The results showed that BPA promoted MCF-7 cell proliferation by activating the ESR1 signaling pathway and upregulated the expression of the downstream key protein Cyclin D1; this effect was abolished by the estrogen receptor antagonist Fulvestrant. In addition, BPA significantly enhanced cell migratory capacity, accompanied by increased EPHA2 expression and alterations in epithelial-mesenchymal transition markers, including increased vimentin expression and decreased E-cadherin expression. Collectively, these findings provide important evidence for understanding the multi-mechanistic pro-proliferative and pro-migratory effects through which BPA may act in estrogen-related tumors, offer new insights into its toxicological mechanisms, and contribute to a better understanding of the molecular basis underlying the potential hazards of BPA exposure.