Modelling the role of dual specificity phosphatases in Herceptin resistant breast cancer cell lines
| Autor: | Jean-Marc Schwartz, Lydia Tabernero, Petronela Buiga, Ari Elson |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Systems biology Antineoplastic Agents Breast Neoplasms Drug resistance Models Biological Biochemistry 03 medical and health sciences 0302 clinical medicine Breast cancer Structural Biology Trastuzumab Cell Line Tumor Dual-specificity phosphatase medicine Humans skin and connective tissue diseases Gene Cell Proliferation biology Mechanism (biology) Cell growth Systems Biology Organic Chemistry Cancer medicine.disease Up-Regulation Gene Expression Regulation Neoplastic Computational Mathematics 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research biology.protein Dual-Specificity Phosphatases medicine.drug |
| Popis: | BackgroundBreast cancer remains the most lethal type of cancer for women. A significant proportion of breast cancer cases are characterised by overexpression of the human epidermal growth factor receptor 2 protein (HER2). These cancers are commonly treated by Herceptin (Trastuzumab), but resistance to drug treatment frequently develops in tumour cells. Dual-specificity phosphatases (DUSPs) are thought to play a role in the mechanism of resistance, since some of them were reported to be overexpressed in tumours resistant to Herceptin.ResultsWe used a systems biology approach to investigate how DUSP overexpression could favour cell proliferation and to predict how this mechanism could be reversed by targeted inhibition of selected DUSPs. We measured the expression of 20 DUSP genes in two breast cancer cell lines following long-term (6 months) exposure to Herceptin, after confirming that these cells had become resistant to the drug. We constructed several Boolean models including specific substrates of each DUSP, and showed that our models correctly account for resistance when overexpressed DUSPs were kept activated. We then simulated inhibition of both individual and combinations of DUSPs, and determined conditions under which the resistance could be reversed.ConclusionsThese results show how a combination of experimental analysis and modelling help to understand cell survival mechanisms in breast cancer tumours, and crucially enable us to generate testable predictions potentially leading to new treatments of resistant tumours. |
| Databáze: | OpenAIRE |
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