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Cited 4 time in webofscience Cited 7 time in scopus
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A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cellsopen access

Authors
Ahmed, MahmoudLai, Trang HuyenKim, WanilKim, Deok Ryong
Issue Date
Dec-2021
Publisher
MDPI
Keywords
metastasis; breast cancer; reverse-causal-reasoning; RKIP; PEBP1
Citation
CANCERS, v.13, no.23
Indexed
SCIE
SCOPUS
Journal Title
CANCERS
Volume
13
Number
23
URI
https://scholarworks.bwise.kr/gnu/handle/sw.gnu/2919
DOI
10.3390/cancers13236098
ISSN
2072-6694
Abstract
Simple Summary We extracted known interactions between metastasis suppressors and their regulators from scientific studies. Next, we used publically available data of drug treatments to identify which of them potentially perturbs these interactions. Finally, we studied the effect of several of these drugs on a particular metastasis suppressor called RKIP and found that our model accurately predicted its regulation in breast cancer cells. Our approach can discover alternative mechanisms of existing cancer drugs and repurpose them in different disease types. Drug screening strategies focus on quantifying the phenotypic effects of different compounds on biological systems. High-throughput technologies have the potential to understand further the mechanisms by which these drugs produce the desired outcome. Reverse causal reasoning integrates existing biological knowledge and measurements of gene and protein abundances to infer their function. This approach can be employed to appraise the existing biological knowledge and data to prioritize targets for cancer therapies. We applied text mining and a manual literature search to extract known interactions between several metastasis suppressors and their regulators. We then identified the relevant interactions in the breast cancer cell line MCF7 using a knockdown dataset. We finally adopted a reverse causal reasoning approach to evaluate and prioritize pathways that are most consistent and responsive to drugs that inhibit cell growth. We evaluated this model in terms of agreement with the observations under treatment of several drugs that produced growth inhibition of cancer cell lines. In particular, we suggested that the metastasis suppressor PEBP1/RKIP is on the receiving end of two significant regulatory mechanisms. One involves RELA (transcription factor p65) and SNAI1, which were previously reported to inhibit PEBP1. The other involves the estrogen receptor (ESR1), which induces PEBP1 through the kinase NME1. Our model was derived in the specific context of breast cancer, but the observed responses to drug treatments were consistent in other cell lines. We further validated some of the predicted regulatory links in the breast cancer cell line MCF7 experimentally and highlighted the points of uncertainty in our model. To summarize, our model was consistent with the observed changes in activity with drug perturbations. In particular, two pathways, including PEBP1, were highly responsive and would be likely targets for intervention.
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