In silico pathway-based drug repurposing for HER2-positive subtype of breast cancer using drug database mining

Introduction & Objectives: Breast cancer is the most frequent cancer and also the leading cause of cancer mortality among women. It subdivides into 4 different types including HER2-positive. Here we intended to use a repurposing strategy to suggest drugs for potential application in breast cancer management.Materials & Methods: Gene expression datasets for different subtypes of breast cancer were extracted from “GEO” database. Data normalization, batch effect removal, and calculation of differential expression of genes were carried out using R software packages. The cut-off criteria used for selecting significant up-regulated genes in HER2 subtype were adjusted p-value<0.05 and log2-fold change>+3. Using Enrichr webserver, gene set enrichment was performed for significant up-regulated genes and significant up-regulated pathways were selected applying adjusted p-value<0.05 filter. The pathways highly associated with breast cancer underwent pathway analysis using KEGG mapper online tool. Critical genes in each pathway were considered as potential therapeutic targets. Drugs for other indications were repositioned for breast cancer treatment using GeneCards database which mines databases including DrugBank, International Union of Basic and Clinical Pharmacology, and The Drug Gene Interaction Database.Results: The up-regulated geneset was mainly associated with cell cycle, IL-17 signaling pathway, pyrimidine metabolism, and cytokine-cytokine receptor interaction. Afterwards, pathway analysis provided the evidence for the likely contribution of PTTG1, CDC6, DBF4, CDK1, TTK, HSP90AB1, CTPS1, TNFRSF12A, and INHBA in breast cancer progression. Finally, Fostamatinib, Alvocidib, Alsterpaullone, DB15498, Bevacizumab, Geldanamycin, and Radicicol were identified as inhibitors of candidate genes.Conclusion: Bevacizumab, an approved medication for breast cancer, included in our proposed drug list may represents a verification for the adopted drug repurposing approach. Therefore, the rest of drugs could potentially be used for breast cancer treatment after passing experimental authentications.

کلیدواژه ها:

Drug repurposing ، pathway analysis ، breast cancer ، HER2+ ، in silico