Increased membrane receptor concentration of HER2 in HER2-overexpressing cells can also activate HER2 by ligand-independent homo-dimerization, leading to activation of the HER2 signalling pathway. HER2 has no known ligand and is activated by dimerization or by incorporation into heterodimers with its related family members HER1, HER3 or HER4. HER2 is a 185 kDa protein that belongs to the family of tyrosine kinase epidermal growth factor receptors, and is also known as Neu or ErbB2. HER2-positive tumours are associated with poor prognosis. Approximately 25% of human breast cancer cases are HER2-positive, due to overexpression of the HER2 protein or amplification of the HER2 gene, or due to activating mutations that increase HER2 activity. This method can be generalized to other drugs and longer time courses to better understand how resistance to drugs develops in cancer cells over time.īreast cancer represents a major public health issue, affecting one in eight women in the Western world. We obtained an understanding of different regulatory pathways in breast cancer and new insights on how these signalling pathways are activated. Conclusionsīoolean modelling is a powerful technique to investigate and understand signalling pathways. Furthermore, we used the models to predict regulatory mechanisms of DUSPs, where these mechanisms were partially known.
In parallel, we built a series of Boolean models representing the known regulatory mechanisms of DUSPs and then demonstrated that the dynamics predicted by the models is in agreement with the experimental data. We clustered these time courses into patterns of similar dynamics over time. We experimentally measured expression time courses of 21 different DUSPs between 0 and 24 h following Herceptin treatment of human MDA-MB-453 HER2-positive breast cancer cells. This study aims to model the initial effects of Herceptin exposure on DUSPs in HER2-positive breast cancer cells using Boolean modelling. Dual specificity phosphatases (DUSPs) are central regulators of cell signalling that function downstream of HER2, but their role in the cellular response to Herceptin is mostly unknown. Understanding the molecular events that occur when breast cancer cells are exposed to Herceptin is therefore of significant importance. Herceptin is a major drug used to treat HER2 positive breast cancer. 25% of breast cancer patients suffer from aggressive HER2-positive tumours that are characterised by overexpression of the HER2 protein or by its increased tyrosine kinase activity.