MDM2 is a Potential Target Gene of Glycyrrhizic Acid for Circumventing Breast Cancer Resistance to Tamoxifen: Integrative Bioinformatics Analysis

Abstract

Background: Tamoxifen is the drug of choice for treating breast cancer, particularly the estrogen receptor-positive luminal A subtype. However, the increased occurrence of Tamoxifen resistance highlights the need to develop an agent to enhance the effectiveness of this drug.

Objective: Although glycyrrhizic acid (GA) is known to exhibit cytotoxic effects on Michigan Cancer Foundation-7 cells, the specific gene targets and pathways it employs to overcome Tamoxifen resistance are incompletely understood. Therefore, the goal of the present research is to discover the potential targets and pathways of GA by using a bioinformatics approach.

Methods: Differentially expressed genes (DEGs) were identified in the Gene Expression Omnibus NCBI database using microarray data from GSE67916 and GSE85871. Further analyses were performed on these DEGs by using DAVID v6.8, STRING-DB v11.0, and Cytoscape v3.8.0. Analysis of gene alterations was performed using cBioPortal for target validation, and the relevant interaction process was examined via the molecular docking method.

Results: Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses identified the PI3K-AKT signaling as the potential target mechanism. Construction of the protein-protein interaction network and analysis of hub genes identified the top 25 hub genes. Genetic alterations were observed in six potential target genes, such as CDK2, MDM2, NF1, SMAD3, PTPN11, and CALM1. Molecular docking analysis demonstrated that the docking score of GA is lower than that of the native ligand of p53. More importantly, 3n the PI3K-AKT signaling pathway is a potential target for overcoming Tamoxifen resistance in breast cancer.

Conclusion: MDM2 may be a potential gene target of GA and the PI3K-AKT signaling may be a prospective mechanism for overcoming Tamoxifen resistance in breast cancer cells. Additional research is required to validate the findings of this study.

Keywords: Bioinformatics; Glycyrrhizic Acid; breast cancer; tamoxifen resistance.

Figure 1

(A) Chemical structure of glycyrrhizic acid (GA). (B) Venn diagram of GA-treated and Tamoxifen-resistant in MCF-7 breast cancer cells

Figure 2

PPI Network of Proteins Related to Pathways that could Overcome Tamoxifen Resistance via Glycyrrhizic Acid as Analyzed by STRING-DB. Degree scores > 5 are marked yellow, while degree scores < 5 are marked blue. A degree score > 5 can facilitate the identification of the top 25 hub genes

Figure 3

Protein Network of top 25 hub Genes, Analyzed by CytoHubba

Figure 4

(A) Frequency of alterations in CDK2, MDM2, NF1, SMAD3, PTPN11, and CALM1 in a genomic dataset obtained from 18 studies of breast cancer. (B) Summary of genetic alterations in CDK2, MDM2, NF1, SMAD3, PTPN11, and CALM1 according to Lefebvre et al. (2016 )

Figure 5

Breast Cancer Pathways Related to Genetically Altered Hub Genes as Analyzed Using the cBioPortal for Cancer Genomics Database

Figure 6

(A) The interaction of GA with MDM2 has a higher docking score than the interaction of the native ligand with the protein, thus indicating lower binding affinity to MDM2. (B) GA interaction with the receptor has more amino acids that are involved than the native. Analyzed using the MOE 2010 molecular docking tool

Figure 7

Prediction of Pathways that could Overcome TamoxifenResistance by Using GA, further interpretation based on the findings and previous research by Miller (2011); Vara (2004); Sarbassov (2005); Mayo (2001); Qiu (2008); Shangary (2008); Wu (2009); Bentz (2019); Khan (2013); and Carter (2007)