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Identification of Target Genes Related to Sulfasalazine in Triple-Negative Breast Cancer Through Network Pharmacology.

ABSTRACT: BACKGROUND The anti-inflammatory drug sulfasalazine (SAS) has been confirmed to inhibit the growth of triple-negative breast cancer (TNBC), but the mechanism is not clear. The aim of this study was to use network pharmacology to find relevant pathways of SAS in TNBC patients. MATERIAL AND METHODS Through screening of the GeneCards, CTD, and ParmMapper databases, potential genes related to SAS and TNBC were identified. In addition, gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed using the R programming language. Protein-protein interaction networks were constructed using Cytoscape. The Kaplan-Meier plotter screened genes related to TNBC prognosis. TNBC patient gene expression profiles and clinical data were downloaded from The Cancer Genome Atlas database. A heatmap was generated using the R programming language that presents the expression of potential target genes in patients with TNBC. RESULTS Eighty potential target genes were identified through multiple databases. The bioinformatical analyses predicted the interrelationships, potential pathways, and molecular functions of the genes from multiple aspects, which are associated with physiological processes such as the inflammatory response, metabolism of reactive oxygen species (ROS), and regulation of proteins in the matrix metalloproteinase (MMP) family. Survival analysis showed that 12 genes were correlated with TNBC prognosis. Heatmapping showed that genes such as those encoding members of the MMP family were differentially expressed in TNBC tissues and normal tissues. CONCLUSIONS Our analysis revealed that the main reasons for the inhibitory effect of SAS on TNBC cells may be inhibition of the inflammatory response and MMP family members and activation of ROS.

SUBMITTER: Yu H

PROVIDER: S-EPMC7513616 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Identification of Target Genes Related to Sulfasalazine in Triple-Negative Breast Cancer Through Network Pharmacology.

Yu Haochen H Hu Ke K Zhang Tao T Ren Haoyu H

Medical science monitor : international medical journal of experimental and clinical research 20200914

BACKGROUND The anti-inflammatory drug sulfasalazine (SAS) has been confirmed to inhibit the growth of triple-negative breast cancer (TNBC), but the mechanism is not clear. The aim of this study was to use network pharmacology to find relevant pathways of SAS in TNBC patients. MATERIAL AND METHODS Through screening of the GeneCards, CTD, and ParmMapper databases, potential genes related to SAS and TNBC were identified. In addition, gene ontology and Kyoto Encyclopedia of Genes and Genomes analyse ...[more]

PMID: 32925871

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Project description:Cancer stem cells (CSCs) are subsets of cells with the ability of self-renewal and differentiation in neoplasm, which are considered to be related to tumor heterogeneity. It has been reported that CSCs act on tumorigenesis and tumor biology of triple-negative breast cancer (TNBC). However, the key genes that cause TNBC showing stem cell characteristics are still unclear. We combined the RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database and mRNA expression-based stemness index (mRNAsi) to further analyze mRNAsi with regard to molecular subtypes, tumor depth, and pathological staging characteristics of breast cancer (BC). Secondly, we extract the differential gene expression of tumor vs. normal group and TNBC vs. other subtypes of BC group, respectively, and intersect them to achieve precise results. We used a weighted gene coexpression network analysis (WGCNA) to screen significant gene modules and the functions of selected genes including BIRC5, CDC25A, KIF18B, KIF2C, ORC1, RAD54L, and TPX2 were carried out through gene ontology (GO) functional annotation. The Oncomine, bc-GenExMiner v4.4, GeneMANIA, Kaplan-Meier Plotter (KM-plotter), and GEPIA were used to verify the expression level and functions of key genes. In this study, we found that TNBC had the highest stem cell characteristics in BC compared with other subtypes. The lower the mRNAsi score, the better the overall survival and treatment outcome. Seven key genes of TNBC were screened and functional annotation indicated that there were strong correlations between them, relating to nuclear division, organelle fission, mitotic nuclear division, and other events that determine cell fate. Among these genes, we found four genes that were highly associated with adverse survival events. Seven key genes identified in this study were found to be closely related to the maintenance of TNBC stemness, and the overexpression of four showed earlier recurrence. The overall survival (OS) curves of all key genes between differential expression level crossed at around nine-year follow-up, which was consistent with the trend of the OS curve related to mRNAsi. These findings may provide new ideas for screening therapeutic targets in order to depress TNBC stemness.

Project description:Objective: Triple-negative breast cancer (TNBC) is a high heterogeneity cancer. The identification of genomic aberrations that drive each of the TNBC subtypes may predict the prognosis of patients with TNBC and provide novel therapeutic strategies in clinical practice. This study focuses on the transcriptome-based gene expression of TNBC and aims to generate comprehensive gene co-expression networks correlated with the immune-related subtype of TNBC. Methods: The transcriptome profiles of 107 female patients with TNBC were analyzed. Weighted gene co-expression network analysis (WGCNA) was applied to construct related networks and to sort hub-genes associated with the survival of TNBC patients. The data of the transcriptional expression, genomic alteration, survival status, and tumor immune microenvironment, which associated with hub-genes, were extracted, retrieved, and analyzed from Oncomine, UALCAN, TCGA, starBase, Kaplan-Meier Plotter, cBioPortal, and TIMER databases. Results: Immune-related hub-genes, including BIRC3, BTN3A1, CSF2RB, GIMAP7, GZMB, HCLS1, LCP2, and SELL, were found to be associated with clinical features of TNBC evaluated by WGCNA. These hub-genes belonged to the immunomodulatory subtype of TNBC and were upregulated in the TNBC cells. The protein expression of eight immune-related hub-genes was further confirmed to be upregulated in TNBC/CD8+ tissues detected by immunohistochemical staining. Survival analysis revealed that overexpression of eight immune-related hub-genes was in favor of the survival of patients with TNBC. Moreover, a positive correlation between eight immune-related hub-genes and immune cell infiltration was observed in TNBC patients. Furthermore, checkpoint inhibitor genes such as PD-L1, PD-1, and CTLA4 were more enrichment in the immunomodulatory subtype of TNBC and the expression of PD-L1, PD-1, and CTLA4 was positively correlated with eight immune-related hub-genes in the breast cancer dataset of TCGA. Conclusions: Eight immune-related hub-genes were identified to be molecular signatures in the immunomodulatory subtype of TNBC, which may provide therapeutic targets for the treatment of patients with breast cancer.

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Project description:Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer, and finite effective therapies. However, the mechanism of Xihuang pill in treating TNBC remains unclear. The present study aims to explore the pharmacological mechanism of Xihuang pill in treating advanced TNBC. We identified the main chemical components of Xihuang pill by using HPLC-Q-TOF-MS/MS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis shows that serum containing Xihuang pill (XS) had no obvious killing effect on any subtype of breast cancer cells, but it inhibited mammosphere colony formation of two TNBC cell lines (4T1 and HCC1806 cells) and could enhance the inhibitory effect of paclitaxel (PTX) on the proliferation of 4T1 and HCC1806 cells when combined with PTX. Seventy-six active compounds in Xihuang pill, their 300 protein targets, and 16667 TNBC stem cell-related genes were identified. The drug-herb-active compound-target gene-disease network and enrichment analyses were constructed with 190 overlapping candidate targets. Through text mining and molecular docking, the target gene NR3C2 and its active compound naringenin were selected for further validation. According to the TCGA database, we observed that a high expression of NR3C2 promoted a higher survival probability regarding overall survival (OS). In vitro experiments indicated that naringenin presented an identical effect to XS, possibly by regulating the NR3C2 expression. Overall, this study explored the effect of Xihuang pill in treating advanced TNBC cells and showed that naringenin, which is the key active compound of Xihuang pill, could lessen the stemness of TNBC cells to produce a synergistic effect on PTX by regulating the NR3C2 gene.

Dataset Information

Identification of Target Genes Related to Sulfasalazine in Triple-Negative Breast Cancer Through Network Pharmacology.

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Identification of Target Genes Related to Sulfasalazine in Triple-Negative Breast Cancer Through Network Pharmacology.

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