AUTHOR=Hermawan Adam , Putri Herwandhani , Hanif Naufa , Fatimah Nurul , Prasetio Heri Himawan 

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

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1019025

DOI=10.3389/fonc.2022.1019025

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>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 <italic>in vitro</italic> experiments, we assessed the target genes of HON against breast cancer resistance to tamoxifen (TAM).</p></sec><sec><title>Materials and methods</title><p>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.</p></sec><sec><title>Results</title><p>PPI network analysis revealed that <italic>FN1</italic>, <italic>FGFR2</italic>, and <italic>RET</italic> were the top three genes with the highest scores. A genetic alteration study of potential target genes revealed <italic>MMP16</italic> and <italic>ERBB4</italic> as the genes with the highest alterations among the breast cancer samples. Pathway enrichment analysis of <italic>FGFR2, RET, ERBB4, SOX2, FN1</italic>, and <italic>MMP16</italic> showed that the genetic alterations herein were likely to impact the RTK-Ras pathway. The expression levels of <italic>RET</italic>, <italic>MMP16</italic>, and <italic>SOX2</italic> 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 <italic>ret</italic>, <italic>ERBB4</italic>, <italic>SOX2</italic>, and <italic>FN1</italic>, as well as the TAM resistance regulatory genes including <italic>HES1</italic>, <italic>VIM</italic>, <italic>PCNA</italic>, <italic>TP53</italic>, and <italic>CASP7</italic>. Molecular docking results indicated that HON tended to bind RET, ErbB4, and the receptor protein Notch1 ankyrin domain more robustly than its native ligand.</p></sec><sec><title>Conclusion</title><p>HON could overcome breast cancer resistance to TAM, potentially by targeting <italic>FGFR2</italic>, <italic>RET</italic>, <italic>ERBB4</italic>, <italic>MMP16</italic>, <italic>FN1</italic>, and <italic>SOX2</italic>. However, further studies are required to validate these results.</p></sec>