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Exploring the Molecular Mechanism of the Drug-Treated Breast Cancer Based on Gene Expression Microarray

Ali Mohamed Alshabi¹, ², Ibrahim Ahmed Shaikh³

¹Department of Clinical Pharmacy, College of Pharmacy, Najran University, Najran, 66237, Saudi Arabia.

|July 18, 2019

Abstract:

: Breast cancer (BRCA) remains the leading cause of cancer morbidity and mortality worldwide. In the present study, we identified novel biomarkers expressed during estradiol and tamoxifen treatment of BRCA. The microarray dataset of E-MTAB-4975 from Array Express database was downloaded, and the differential expressed genes (DEGs) between estradiol-treated BRCA sample and tamoxifen-treated BRCA sample were identified by limma package. The pathway and gene ontology (GO) enrichment analysis, construction of protein-protein interaction (PPI) network, module analysis, construction of target genes-miRNA interaction network and target genes-transcription factor (TF) interaction network were performed using bioinformatics tools. The expression, prognostic values, and mutation of hub genes were validated by SurvExpress database, cBioPortal, and human protein atlas (HPA) database. A total of 856 genes (421 up-regulated genes and 435 down-regulated genes) were identified in T47D (overexpressing Split Ends (SPEN) + estradiol) samples compared to T47D (overexpressing Split Ends (SPEN) + tamoxifen) samples. Pathway and GO enrichment analysis revealed that the DEGs were mainly enriched in response to lysine degradation II (pipecolate pathway), cholesterol biosynthesis pathway, cell cycle pathway, and response to cytokine pathway. DEGs (MCM2, TCF4, OLR1, HSPA5, MAP1LC3B, SQSTM1, NEU1, HIST1H1B, RAD51, RFC3, MCM10, ISG15, TNFRSF10B, GBP2, IGFBP5, SOD2, DHF and MT1H) , which were significantly up- and down-regulated in estradiol and tamoxifen-treated BRCA samples, were selected as hub genes according to the results of protein-protein interaction (PPI) network, module analysis, target genes-miRNA interaction network and target genes-TF interaction network analysis. The SurvExpress database, cBioPortal, and Human Protein Atlas (HPA) database further confirmed that patients with higher expression levels of these hub genes experienced a shorter overall survival. A comprehensive bioinformatics analysis was performed, and potential therapeutic applications of estradiol and tamoxifen were predicted in BRCA samples. The data may unravel the future molecular mechanisms of BRCA.

Insights

This study identified novel biomarkers in breast cancer (BRCA) treated with estradiol and tamoxifen. These biomarkers, including MCM2 and RAD51, are linked to shorter survival, offering potential therapeutic targets for BRCA.

Area of Science:

Oncology
Genomics
Bioinformatics

Background:

Breast cancer (BRCA) is a major global health concern, driving research into effective treatments.
Estradiol and tamoxifen are key therapeutic agents, necessitating a deeper understanding of their molecular effects on BRCA.

Purpose of the Study:

To identify novel biomarkers associated with estradiol and tamoxifen treatment in BRCA.
To elucidate the molecular mechanisms and prognostic implications of these biomarkers.

Main Methods:

Downloaded and analyzed microarray data (E-MTAB-4975) to identify differentially expressed genes (DEGs).
Utilized bioinformatics tools for pathway and Gene Ontology (GO) enrichment analysis, and constructed protein-protein interaction (PPI), miRNA, and transcription factor (TF) networks.
Validated hub gene expression, prognostic values, and mutations using SurvExpress, cBioPortal, and Human Protein Atlas (HPA) databases.

Main Results:

Identified 856 DEGs (421 up-regulated, 435 down-regulated) in estradiol-treated versus tamoxifen-treated BRCA samples.
Enriched pathways included lysine degradation, cholesterol biosynthesis, cell cycle, and cytokine response.
Selected 18 hub genes (e.g., MCM2, TCF4, RAD51) significantly associated with patient survival, with higher expression correlating to shorter overall survival.

Conclusions:

Identified novel prognostic biomarkers in BRCA treated with estradiol and tamoxifen.
These findings provide insights into molecular mechanisms and potential therapeutic strategies for BRCA.

Read full analysis

Keywords:

microRNA pathway enrichment analysis protein-protein interaction network

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