A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells
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 biol...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/23/6098 |
| _version_ | 1797507930192347136 |
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| author | Mahmoud Ahmed Trang Huyen Lai Wanil Kim Deok Ryong Kim |
| author_facet | Mahmoud Ahmed Trang Huyen Lai Wanil Kim Deok Ryong Kim |
| author_sort | Mahmoud Ahmed |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:55:25Z |
| format | Article |
| id | doaj.art-91729af46cc642cb99532d54fcfae443 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:55:25Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-91729af46cc642cb99532d54fcfae4432023-11-23T02:14:36ZengMDPI AGCancers2072-66942021-12-011323609810.3390/cancers13236098A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer CellsMahmoud Ahmed0Trang Huyen Lai1Wanil Kim2Deok Ryong Kim3Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, KoreaDepartment of Biochemistry and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, KoreaDepartment of Biochemistry and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, KoreaDepartment of Biochemistry and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, KoreaDrug 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.https://www.mdpi.com/2072-6694/13/23/6098metastasisbreast cancerreverse-causal-reasoningRKIP/PEBP1 |
| spellingShingle | Mahmoud Ahmed Trang Huyen Lai Wanil Kim Deok Ryong Kim A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells Cancers metastasis breast cancer reverse-causal-reasoning RKIP/PEBP1 |
| title | A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells |
| title_full | A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells |
| title_fullStr | A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells |
| title_full_unstemmed | A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells |
| title_short | A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells |
| title_sort | functional network model of the metastasis suppressor pebp1 rkip and its regulators in breast cancer cells |
| topic | metastasis breast cancer reverse-causal-reasoning RKIP/PEBP1 |
| url | https://www.mdpi.com/2072-6694/13/23/6098 |
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