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

Zeinab  Dehghan; Seyed Amir  Mirmotalebisohi; Marzieh  Sameni; Maryam   Bazgiri; Hakimeh  Zali

doi:10.18502/ajmb.v14i2.8889

Zeinab Dehghan Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Seyed Amir Mirmotalebisohi Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Marzieh Sameni Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Maryam Bazgiri Department of Animal Science, Agriculture and Natural Resources University of Khuzestan, Ahvaz, Iran
Hakimeh Zali Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

DOI: https://doi.org/10.18502/ajmb.v14i2.8889

Keywords: Breast cancer, Doxorubicin, Protein-protein interaction network, Regulatory motif, Systems biology

Abstract

Background: Breast cancer is the most common malignancy worldwide. Doxorubicin is an anthracycline used to treat breast cancer as the first treatment choice. Nevertheless, the molecular mechanisms underlying the response to Doxorubicin and its side effects are not comprehensively understood so far. We used systems biology and bioinformatics 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 identify 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 induction, DNA repair, invasion inhibition, metastasis, and DNA replication are suggested 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 molecular mechanisms and side effects underlying the response to Doxorubicin in breast cancer requiring further investigations.