Integrative Bioinformatics Analysis Reveals Potential Target Genes and TNFα Signaling Inhibition by Brazilin in Metastatic Breast Cancer Cells.

Adam Hermawan,Herwandhani Putri

doi:10.31557/apjcp.2020.21.9.2751

Abstract

Objective:Metastasis is the most significant cause of morbidity and mortality in breast cancer patients. Previously, a combination of brazilin and doxorubicin has been shown to inhibit metastasis in HER2-positive breast cancer cells. This present study used an integrative bioinformatics approach to identify new targets and the molecular mechanism of brazilin in inhibiting metastasis in breast cancer. Methods:Cytotoxicity and mRNA arrays data were retreived from the DTP website, whereas genes that regulate metastatic breast cancer cells were retreived from PubMed with keywords “breast cancer metastasis”. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Drug association analysis were carried out by using WEB-based GEne SeT AnaLysis Toolkit (WebGestalt). Construction of protein-protein interaction (PPI) network analysis was performed by STRING-DB v11.0 and Cytoscape, respectively. The genetic alterations of the potential therapeutic target genes of brazilin (PB) were analyzed using cBioPortal. Results:Analysis of cytotoxicity with the public database of COMPARE showed that brazilin exerts almost the same cytotoxicity in the NCI-60 cells panel showing by similar GI50 value, in which the lowest GI50 value was observed in MDA-MB 231, a metastatic breast cancer cells. KEGG enrichment indicated several pathways regulated by brazilin such as TNF signaling pathway, cellular senescence, and pathways in cancer. We found ten drugs that are associated with PB, including protein kinase inhibitors, TNFα inhibitors, enzyme inhibitors, and anti-inflammatory agents. Conclusion:In conclusion, this study identified eight PB, including MMP14, PTGS2, ADAM17, PTEN, CCL2, PIK3CB, MAP3K8, and CXCL3. In addition, brazilin possibly inhibits metastatic breast cancer through inhibition of TNFα signaling. The study results study need to be validated with in vitro and in vivo studies to strengthen scientific evidence of the use of brazilin in breast cancer metastasis inhibition.

Highlights

Metastasis is the most significant cause of morbidity and mortality in breast cancer patients (Yousefi et al, 2018)
Analysis of cytotoxicity with the public database of COMPARE showed that brazilin exerts almost the same cytotoxicity in the NCI-60 cells panel showing by similar GI50 value, in which the lowest GI50 value was observed in MDA-MB 231, a metastatic breast cancer cells
COMPARE analysis revealed 1249 genes regulated by brazilin (Supplementary Table 3), including 587 and 662 genes with the positive and negative Pearson correlation coefficient, respectively

Summary

Introduction

Metastasis is the most significant cause of morbidity and mortality in breast cancer patients (Yousefi et al, 2018). The first-line treatment for metastases in breast cancer is chemotherapy (Telli and Carlson, 2009); its prolonged use induces side effects, such as cardiotoxicity (Shafei et al, 2017) and suppression of immune system (Larsson et al, 2019). The effectivity of chemotherapy in breast cancer treatment decrease due to intrinsic and acquired chemoresistance, which leads to relapse and metastasis (Rivera and Gomez, 2010). Developing a strategy that can overcome the progression and metastasis of breast cancer cells is necessary, including the development of new drugs from natural products. The combination of brazilin and doxorubicin has been shown to inhibit metastasis in HER2-positive breast cancer through downregulation of MMP9, MMP2, and Rac (Jenie et al, 2018). Breast cancer is a complex disease (Fragomeni et al, 2018) and the mechanisms of metastasis involve many key proteins (Welch and Hurst, 2019), and discover new

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Conclusion