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Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer
Accurate identification of molecular targets of disease plays an important role in diagnosis, prognosis, and therapies. Breast cancer (BC) is one of the most common malignant cancers in women worldwide. Thus, the objective of this study was to accurately identify a set of molecular targets and small...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531711/ https://www.ncbi.nlm.nih.gov/pubmed/36204232 http://dx.doi.org/10.3389/fphar.2022.942126 |
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author | Alam, Md Shahin Sultana, Adiba Sun, Hongyang Wu, Jin Guo, Fanfan Li, Qing Ren, Haigang Hao, Zongbing Zhang, Yi Wang, Guanghui |
author_facet | Alam, Md Shahin Sultana, Adiba Sun, Hongyang Wu, Jin Guo, Fanfan Li, Qing Ren, Haigang Hao, Zongbing Zhang, Yi Wang, Guanghui |
author_sort | Alam, Md Shahin |
collection | PubMed |
description | Accurate identification of molecular targets of disease plays an important role in diagnosis, prognosis, and therapies. Breast cancer (BC) is one of the most common malignant cancers in women worldwide. Thus, the objective of this study was to accurately identify a set of molecular targets and small molecular drugs that might be effective for BC diagnosis, prognosis, and therapies, by using existing bioinformatics and network-based approaches. Nine gene expression profiles (GSE54002, GSE29431, GSE124646, GSE42568, GSE45827, GSE10810, GSE65216, GSE36295, and GSE109169) collected from the Gene Expression Omnibus (GEO) database were used for bioinformatics analysis in this study. Two packages, LIMMA and clusterProfiler, in R were used to identify overlapping differential expressed genes (oDEGs) and significant GO and KEGG enrichment terms. We constructed a PPI (protein–protein interaction) network through the STRING database and identified eight key genes (KGs) EGFR, FN1, EZH2, MET, CDK1, AURKA, TOP2A, and BIRC5 by using six topological measures, betweenness, closeness, eccentricity, degree, MCC, and MNC, in the Analyze Network tool in Cytoscape. Three online databases GSCALite, Network Analyst, and GEPIA were used to analyze drug enrichment, regulatory interaction networks, and gene expression levels of KGs. We checked the prognostic power of KGs through the prediction model using the popular machine learning algorithm support vector machine (SVM). We suggested four TFs (TP63, MYC, SOX2, and KDM5B) and four miRNAs (hsa-mir-16-5p, hsa-mir-34a-5p, hsa-mir-1-3p, and hsa-mir-23b-3p) as key transcriptional and posttranscriptional regulators of KGs. Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients. |
format | Online Article Text |
id | pubmed-9531711 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95317112022-10-05 Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer Alam, Md Shahin Sultana, Adiba Sun, Hongyang Wu, Jin Guo, Fanfan Li, Qing Ren, Haigang Hao, Zongbing Zhang, Yi Wang, Guanghui Front Pharmacol Pharmacology Accurate identification of molecular targets of disease plays an important role in diagnosis, prognosis, and therapies. Breast cancer (BC) is one of the most common malignant cancers in women worldwide. Thus, the objective of this study was to accurately identify a set of molecular targets and small molecular drugs that might be effective for BC diagnosis, prognosis, and therapies, by using existing bioinformatics and network-based approaches. Nine gene expression profiles (GSE54002, GSE29431, GSE124646, GSE42568, GSE45827, GSE10810, GSE65216, GSE36295, and GSE109169) collected from the Gene Expression Omnibus (GEO) database were used for bioinformatics analysis in this study. Two packages, LIMMA and clusterProfiler, in R were used to identify overlapping differential expressed genes (oDEGs) and significant GO and KEGG enrichment terms. We constructed a PPI (protein–protein interaction) network through the STRING database and identified eight key genes (KGs) EGFR, FN1, EZH2, MET, CDK1, AURKA, TOP2A, and BIRC5 by using six topological measures, betweenness, closeness, eccentricity, degree, MCC, and MNC, in the Analyze Network tool in Cytoscape. Three online databases GSCALite, Network Analyst, and GEPIA were used to analyze drug enrichment, regulatory interaction networks, and gene expression levels of KGs. We checked the prognostic power of KGs through the prediction model using the popular machine learning algorithm support vector machine (SVM). We suggested four TFs (TP63, MYC, SOX2, and KDM5B) and four miRNAs (hsa-mir-16-5p, hsa-mir-34a-5p, hsa-mir-1-3p, and hsa-mir-23b-3p) as key transcriptional and posttranscriptional regulators of KGs. Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients. Frontiers Media S.A. 2022-09-20 /pmc/articles/PMC9531711/ /pubmed/36204232 http://dx.doi.org/10.3389/fphar.2022.942126 Text en Copyright © 2022 Alam, Sultana, Sun, Wu, Guo, Li, Ren, Hao, Zhang and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Alam, Md Shahin Sultana, Adiba Sun, Hongyang Wu, Jin Guo, Fanfan Li, Qing Ren, Haigang Hao, Zongbing Zhang, Yi Wang, Guanghui Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer |
title | Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer |
title_full | Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer |
title_fullStr | Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer |
title_full_unstemmed | Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer |
title_short | Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer |
title_sort | bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531711/ https://www.ncbi.nlm.nih.gov/pubmed/36204232 http://dx.doi.org/10.3389/fphar.2022.942126 |
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