PT  - JOURNAL ARTICLE
AU  - Regan Odongo
AU  - Asuman Demiroglu Zergeroglu
AU  - Tunahan Cakir
TI  - A Systems Pharmacology Approach based on Oncogenic Signalling Pathways to Determine the Mechanisms of Action of Natural Products in Breast Cancer from Transcriptome Data
AID  - 10.1101/2020.04.18.048454
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.18.048454
4099  - http://biorxiv.org/content/early/2020/04/20/2020.04.18.048454.short
4100  - http://biorxiv.org/content/early/2020/04/20/2020.04.18.048454.full
AB  - Background Plant-derived natural products possess poly-pharmacologic mechanisms of action with good tolerability and thus are appropriate in the management of complex diseases, especially cancers. However, methodological limitations impede attempts to catalogue targeted processes and infer systemic mechanisms of action. Integrative systems biology approaches are better suited in these cases due to their analytical comprehensiveness.Method The transcriptome data from drug-treated breast cancer cell lines were mapped on human protein interactome to construct targeted subnetworks. The subnetworks were analysed in terms of enriched oncogenic signalling pathways by reducing redundancy through pathway-pathway interaction networks, and the filtered pathways were mapped on oncogenesis processes.Results The signalling pathways regulated by the pleiotropic effects of Actein, Withaferin A, Indole-3-Carbinol and Compound Kushen were found to be projected on a set of oncogenesis processes at the transcriptomic level in different breast cancer subtypes (triple negative, luminal A and HER2+). Notably, these compounds indirectly regulated known oncogenes in the different subtypes through their associated pathways in the subnetworks.Conclusion The proposed approach infers the mechanisms of action from enriched subnetworks and oncogenic signalling pathways and provides a systematic approach for evaluating poly-pharmacologic compounds.Competing Interest StatementThe authors have declared no competing interest.