A systems pharmacology approach based on oncogenic signalling pathways to determine the mechanisms of action of natural products in breast cancer from transcriptome data

Background Narrow spectrum of action through limited molecular targets and unforeseen drug-related toxicities have been the main reasons for drug failures at the phase I clinical trials in complex diseases. Most plant-derived compounds with medicinal values possess poly-pharmacologic properties with overall 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. While most of the current understanding of these compounds is based on reductive methods, it is increasingly becoming clear that holistic techniques, leveraging current improvements in omic data collection and bioinformatics methods, are better suited for elucidating their systemic effects. Thus, we developed and implemented an integrative systems biology pipeline to study these compounds and reveal their mechanism of actions on breast cancer cell lines. Methods Transcriptome data from compound-treated breast cancer cell lines, representing triple negative (TN), luminal A (ER+) and HER2+ tumour types, were mapped on human protein interactome to construct targeted subnetworks. The subnetworks were analysed for enriched oncogenic signalling pathways. Pathway redundancy was reduced by constructing pathway-pathway interaction networks, and the sets of overlapping genes were subsequently used to infer pathway crosstalk. The resulting filtered pathways were mapped on oncogenesis processes to evaluate their anti-carcinogenic effectiveness, and thus putative mechanisms of action. Results The signalling pathways regulated by Actein, Withaferin A, Indole-3-Carbinol and Compound Kushen, which are extensively researched compounds, were shown to be projected on a set of oncogenesis processes at the transcriptomic level in different breast cancer subtypes. The enrichment of well-known tumour driving genes indicate that these compounds indirectly dysregulate cancer driving pathways in the subnetworks. Conclusion The proposed framework infers the mechanisms of action of potential drug candidates from their enriched protein interaction subnetworks and oncogenic signalling pathways. It also provides a systematic approach for evaluating such compounds in polygenic complex diseases. In addition, the plant-based compounds used here show poly-pharmacologic mechanism of action by targeting subnetworks enriched with cancer driving genes. This network perspective supports the need for a systemic drug-target evaluation for lead compounds prior to efficacy experiments.

Signal Transduction of a Novel WBP2 Oncogene

WW-domain binding protein 2 (WBP2) was first discovered as a ligand of the WW-domain of Yes-associated Protein (YAP). A decade after its discovery, our laboratory implicated WBP2 in breast cancer development. Since then, WBP2 had also been shown to be involved in other types of cancer, such as glioma, liver and skin cancer. The oncogenic properties of WBP2 are mediated by several oncogenic signalling pathways, including EGFR, PI3K/Akt, ER, Wnt, and Hippo signalling pathways. Recently, WBP2 was demonstrated to play roles in diseases other than cancer, such as infertility and deafness. In the near future, we envisage a growing body of literature surrounding the role of WBP2 in more cancer types and signalling pathways.

Cytoskeletal Proteins in Cancer and Intracellular Stress: A Therapeutic Perspective

Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules, actin and intermediate filaments, are essential for survival and cellular processes in both normal as well as cancer cells. However, in cancer cells, these mechanisms can be altered to promote tumour development and progression, whereby the functions of cytoskeletal proteins are co-opted to facilitate increased migrative and invasive capabilities, proliferation, as well as resistance to cellular and environmental stresses. Herein, we discuss the cytoskeletal responses to important intracellular stresses (such as mitochondrial, endoplasmic reticulum and oxidative stresses), and delineate the consequences of these responses, including effects on oncogenic signalling. In addition, we elaborate how the cytoskeleton and its associated molecules present themselves as therapeutic targets. The potential and limitations of targeting new classes of cytoskeletal proteins are also explored, in the context of developing novel strategies that impact cancer progression.