en 35633986 <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:9.5pt">Background:</span><span style="font-size:10.0pt"> 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</span> <span style="font-size:10.0pt">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. </span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:9.5pt">Methods:</span><span style="font-size:10.0pt"> 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. </span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:9.5pt">Results:</span><span style="font-size:10.0pt"> 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. </span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:9.5pt">Conclusion:</span><span style="font-size:10.0pt"> 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.</span></span></p> Breast cancer, Doxorubicin, Protein-protein interaction network, Regulatory motif, Systems biology 137 153 https://www.ajmb.org/En/Article.aspx?id=60497 https://www.ajmb.org/PDF/En/FullText/60497.pdf Zeinab Dehghan Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran91845Seyed Amir MirmotalebisohiCellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran91846MarziehSameniCellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran91847MaryamBazgiriDepartment of Animal Science, Agriculture and Natural Resources University of Khuzestan, Ahvaz, Iran91848HakimehZaliDepartment of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran91849