Avicenna J Med Biotech

arij002

Avicenna Journal of Medical Biotechnology

2008-2835 2008-4625

Avicenna Research Institute

ajmb60497

A Motif-Based Network Analysis of Regulatory Patterns in Doxorubicin Effects on Treating Breast Cancer, a Systems Biology Study

Dehghan

Zeinab

Mirmotalebisohi

Seyed Amir

Sameni

Marzieh

Bazgiri

Maryam

Zali

Hakimeh

14 2 137 153 16 10 2021 22 1 2022

Background: Breast cancer is the most common malignancy worldwide. Doxorubicin is an anthracycline used to treat breast cancer as the first treatment choice. Never-theless, the molecular mechanisms underlying the response to Doxorubicin and its side effects are not comprehensively understood so far. We used systems biology and bio-informatics methods to identify essential genes and molecular mechanisms behind the body response to Doxorubicin and its side effects in breast cancer patients. Methods: Omics data were extracted and analyzed to construct the protein-protein interaction and gene regulatory networks. Network analysis was performed to iden-tify hubs, bottlenecks, clusters, and regulatory motifs to evaluate crucial genes and molecular mechanisms behind the body response to Doxorubicin and its side effects. Results: Analyzing the constructed PPI and gene-TF-miRNA regulatory network showed that MCM3, MCM10, and TP53 are key hub-bottlenecks and seed proteins. Enrichment analysis also revealed cell cycle, TP53 signaling, Forkhead box O (FoxO) signaling, and viral carcinogenesis as essential pathways in response to this drug. Besides, SNARE interactions in vesicular transport and neurotrophin signaling were identified as pathways related to the side effects of Doxorubicin. The apoptosis in-duction, DNA repair, invasion inhibition, metastasis, and DNA replication are sug-gested as critical molecular mechanisms underlying Doxorubicin anti-cancer effect. SNARE interactions in vesicular transport and neurotrophin signaling and FoxO signaling pathways in glucose metabolism are probably the mechanisms responsible for side effects of Doxorubicin. Conclusion: Following our model validation using the existing experimental data, we recommend our other newly predicted biomarkers and pathways as possible mole-cular mechanisms and side effects underlying the response to Doxorubicin in breast cancer requiring further investigations.