Abstract
Background25% 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. Herceptin is a major drug used to treat HER2 positive breast cancer. Understanding the molecular events that occur when breast cancer cells are exposed to Herceptin is therefore of significant importance. 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. This study aims to model the initial effects of Herceptin exposure on DUSPs in HER2-positive breast cancer cells using Boolean modelling.ResultsWe 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. We clustered these time courses into patterns of similar dynamics over time. 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. Furthermore, we used the models to predict regulatory mechanisms of DUSPs, where these mechanisms were partially known.ConclusionsBoolean modelling is a powerful technique to investigate and understand signalling pathways. We obtained an understanding of different regulatory pathways in breast cancer and new insights on how these signalling pathways are activated. 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.
Highlights
Breast cancer represents a major public health issue, affecting one in eight women in the Western world [1]
Dual specificity phosphatases (DUSPs) expression measured by qPCR We measured gene expression of 21 DUSPs (10 MAPK phosphatases (MKPs) and atypical DUSPs) by RT-qPCR in the human HER2-positive MDA-MB-453 breast cancer cell line at 0, 2, 4, and 24 h following Herceptin exposure
We limited our analysis to 24 h in order to focus on the initial response in DUSP gene expression and cell signalling to Herceptin
Summary
Breast cancer represents a major public health issue, affecting one in eight women in the Western world [1]. 25% of human breast cancer cases are HER2positive, due to overexpression of the HER2 protein or amplification of the HER2 gene, or due to activating mutations that increase HER2 activity. HER2-positive tumours are associated with poor prognosis [2, 3]. HER2 is a 185 kDa protein that belongs to the family of tyrosine. A major drug for treating HER2-positive breast cancer is Herceptin, a humanized monoclonal antibody that binds the extracellular Domain IV of HER2. Herceptin reduces HER2 dimerization leading to, among other effects, inhibition of MAPK signalling [6]. Herceptin has high efficacy in patients with HER2-positive breast cancer, but resistance to its effects often develops and poses a significant therapeutic challenge [7, 8]
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