Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen.

BACKGROUND

Honokiol (HON) inhibits epidermal growth factor receptor (EGFR) signaling and increases the activity of erlotinib, an EGFR inhibitor, in human head and neck cancers. In this study, using a bioinformatics approach and experiments, we assessed the target genes of HON against breast cancer resistance to tamoxifen (TAM).

MATERIALS AND METHODS

Microarray data were obtained from GSE67916 and GSE85871 datasets to identify differentially expressed genes (DEGs). DEGs common between HON-treated and TAM-resistant cells were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and protein-protein interaction (PPI) networks were constructed. Selected genes were analyzed for genetic alterations, expression, prognostic value, and receiver operating characteristics (ROC). TAM-resistant MCF-7 (MCF-7 TAM-R) cells were generated and characterized for their resistance toward TAM. A combination of HON and TAM was used for cytotoxicity and gene expression analyses. Molecular docking was performed using the Molecular Operating Environment software.

RESULTS

PPI network analysis revealed that , , and were the top three genes with the highest scores. A genetic alteration study of potential target genes revealed and as the genes with the highest alterations among the breast cancer samples. Pathway enrichment analysis of , and showed that the genetic alterations herein were likely to impact the RTK-Ras pathway. The expression levels of , , and were strongly correlated with prognostic power, with areas under the ROC curves (AUC) ​​of 1, 0.8, and 0.8, respectively. The HON and TAM combination increased TAM cytotoxicity in MCF-7 TAM-R cells by regulating the expression of potential target genes , , , and , as well as the TAM resistance regulatory genes including , , , , and . Molecular docking results indicated that HON tended to bind RET, ErbB4, and the receptor protein Notch1 ankyrin domain more robustly than its native ligand.

CONCLUSION

HON could overcome breast cancer resistance to TAM, potentially by targeting , , , , , and . However, further studies are required to validate these results.