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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
A Motif-Based Network Analysis of Regulatory Patterns in Doxorubicin Effects on Treating Breast Cancer, a Systems
Zeinab Dehghan1,2, Seyed Amir Mirmotalebisohi1,2, Marzieh Sameni1,2
1Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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.
Insights
This study identifies key genes and pathways involved in breast cancer response to doxorubicin. Findings reveal mechanisms for both anti-cancer effects and side effects, guiding future research.
Area of Science:
- Oncology
- Bioinformatics
- Systems Biology
Background:
- Breast cancer is a leading global malignancy.
- Doxorubicin is a primary treatment, but its mechanisms and side effects require further understanding.
- Systems biology and bioinformatics approaches are employed to elucidate these processes.
Purpose of the Study:
- To identify essential genes and molecular mechanisms driving the response to doxorubicin in breast cancer.
- To uncover pathways associated with doxorubicin's therapeutic effects and its adverse side effects.
- To provide a foundation for novel biomarker and therapeutic target discovery.
Main Methods:
- Construction and analysis of protein-protein interaction (PPI) and gene regulatory networks.
- Identification of key genes (hubs, bottlenecks) and regulatory motifs.
- Pathway enrichment analysis to determine significant biological processes.
Main Results:
- MCM3, MCM10, and TP53 identified as crucial hub proteins.
- Key pathways include cell cycle, TP53 signaling, Forkhead box O (FoxO) signaling, and viral carcinogenesis.
- SNARE interactions and neurotrophin signaling implicated in doxorubicin's side effects.
Conclusions:
- Doxorubicin's anti-cancer effects involve apoptosis, DNA repair, and metastasis inhibition.
- FoxO signaling and SNARE interactions may mediate doxorubicin-induced side effects.
- Predicted biomarkers and pathways warrant further investigation for clinical relevance.
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