Document Type : Original Article(s)

Authors

• Mohadeseh Khoshandam ¹
• Mohammad Rahmanian ^{2, 3}
• Mohammad Taghi Hedayati Goudarzi ⁴
• Hossein Soltaninejad ⁵
• Sadegh Babashah ⁶
• Mahdiye Khoshandam ⁷

¹ Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran

² Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

³ Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

⁴ Department of Cardiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran

⁵ Department of Stem Cells Technology and Tissue Regeneration, Faculty of Interdisciplinary Science and Technologies, Tarbiat Modares University, Tehran, Iran

⁶ Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

⁷ Department of Cell Biology and Regenerative Medicine, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran

Abstract

Background: Breast cancer is the most common form of cancer among women worldwide, and the rates of both new cases and deaths have increased over the past two decades. The aim of the study was to identify and validate molecular pathways that could potentially be targeted for therapeutic interventions. 
Methods: The bioinformatics resource WebGestalt was used to determine the functional annotation of the Gene Ontology, as well as enrichment analysis of Reactome and KEGG pathways in 2023-2024. GeneMANIA, a server for assessing protein-gene interactions, co-localization, pathways, co-expression, and protein-domain similarity of target genes and their interacting genes, was evaluated via this web tool. GEO was also used to determine mRNA expression levels in BRCA individuals. R packages were used to screen for differentially expressed genes for both datasets. On the other hand, the open cancer resources GENT2 TNMPlot, UCSCXena, ENCORI platform, BioXpress, OncoDB, OncoMX, and GEPIA2 were used to measure the differential expression of mRNAs in BRCA patients.
Results: Among the genes analyzed, matrix metalloproteinase-9 (MMP9) showed the greatest change. Similarly, matrix metallopeptidase 14 (MMP14) and Endogenous Vascular Endothelial Growth Factor-A (VEGFA) showed significant increases. Other up-regulated genes, including Apolipoprotein E (APOE), Hypoxia-Inducible Factor-1 Alpha (HIF1A), and Tumor Necrosis Factor (TNF) showed minimal expression changes with minor fluctuations. Finally, Interleukin-1 alpha precursor (IL1A) exhibited a slight increase in expression. Validation of gene expression changes through microarray studies on the GSE37751 and GSE42568 datasets provided consistent and significant results for several of the studied genes. GO analysis further revealed significant molecular functions, cellular components, KEGG pathways, and biological processes that were enriched among the differentially expressed genes. Among the top pathways identified based on FDR and P value were receptor binding signaling, regulation of cell migration, the extracellular matrix, and the AGE-RAGE signaling pathway.
Conclusion: The results predict that the hub genes correlated with angiogenesis may serve as potential therapeutic targets or could be biomarkers for breast cancer.

Highlights

Mohadeseh Khoshandam (Google Scholar) 
Hossein Soltaninejad (Google Scholar) 

Keywords

• Breast neoplasms
• Vascular endothelial growth factor A
• Gene regulatory networks