Objective To investigate the effects of bisphenol A (BPA) and its substitutes on the expression of key genes involved in the proliferation and migration of breast cancer cells through bioinformatics analysis and in-vitro experiments.

Methods The differentially expressed genes (DEGs) of human breast cancer MCF-7 cells induced by BPA and its substitutes were determined through the GSE number in the Gene Expression Omnibus database GSE85350. Functional enrichment analysis and visualization were performed on the DEGs using clusterProfiler and enrichplot packages in R 4.2.3, followed by identifying hub genes and protein-protein interaction network construction conducted through the maximal clique centrality (MCC) algorithm. The expression of key genes in human breast cancer samples was further verified by Gene Expression Profiling Interactive Analysis. Finally, the mRNA expression levels of the key DEGs were verified using real-time quantitative polymerase chain reaction.

Results The gene ontology analysis of DEGs revealed that 27 DEGs in the BPA exposure group were mainly enriched in spindle organization and myotube differentiation; 65 DEGs in the BPF exposure group were mainly enriched in steroid response and positive regulation of cell-substrate adhesion; and 185 DEGs in the BPS exposure group were enriched in organelle fission and nuclear division. Twenty-four BPB-induced DEGs, 23 BPAF-induced DEGs, and 101 shared DEGs were not enriched. According to the protein interaction network and the core genes identified from shared DEGs with the MCC algorithm, exposure to BPA and its substitutes could influence the expression of genes associated with the proliferation and migration of human breast cancer MCF-7 cells, including CD44, PPARG, EPAS1, CDK6, PGR, RET, CDKN2B, LDHA, ALDH1A3, and SALL4.

Conclusion Exposure to BPA and its substitutes can promote the mRNA expression of the CD44, PGR, RET, and LDHA genes, and inhibit the mRNA expression of the PPARG, EPAS1, CDK6, CDKN2B, ALDH1A3, and SALL4 genes.