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Open AccessArticle

Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer

School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Author to whom correspondence should be addressed.
Genes 2019, 10(8), 568;
Received: 26 June 2019 / Revised: 18 July 2019 / Accepted: 19 July 2019 / Published: 26 July 2019
Background: HER2 (human epidermal growth factor 2)-positive breast cancer is an aggressive type of breast cancer characterized by the overexpression of the receptor-type protein tyrosine kinase HER2 or amplification of the HER2 gene. It is commonly treated by the drug trastuzumab (Herceptin), but resistance to its action frequently develops and limits its therapeutic benefit. Dual-specificity phosphatases (DUSPs) were previously highlighted as central regulators of HER2 signaling; therefore, understanding their role is crucial to designing new strategies to improve the efficacy of Herceptin treatment. We investigated whether inhibiting certain DUSPs re-sensitized Herceptin-resistant breast cancer cells to the drug. We built a series of kinetic models incorporating the key players of HER2 signaling pathways and simulating a range of inhibition intensities. The simulation results were compared to live tumor cells in culture, and showed good agreement with the experimental analyses. In particular, we observed that Herceptin-resistant DUSP16-silenced breast cancer cells became more responsive to the drug when treated for 72 h with Herceptin, showing a decrease in resistance, in agreement with the model predictions. Overall, we showed that the kinetic modeling of signaling pathways is able to generate predictions that assist experimental research in the identification of potential targets for cancer treatment. View Full-Text
Keywords: kinetic model; breast cancer; Herceptin; dual-specificity phosphatases kinetic model; breast cancer; Herceptin; dual-specificity phosphatases
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Buiga, P.; Elson, A.; Tabernero, L.; Schwartz, J.-M. Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer. Genes 2019, 10, 568.

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