PT  - JOURNAL ARTICLE
AU  - Petronela Buiga
AU  - Ari Elson
AU  - Lydia Tabernero
AU  - Jean-Marc Schwartz
TI  - Modelling the role of dual specificity phosphatases in Herceptin resistant breast cancer cell lines
AID  - 10.1101/528315
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 528315
4099  - http://biorxiv.org/content/early/2019/01/23/528315.short
4100  - http://biorxiv.org/content/early/2019/01/23/528315.full
AB  - Background Breast 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.Results We 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.Conclusions These 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.