Please use this identifier to cite or link to this item: doi:10.22028/D291-30771
Title: Mathematical modeling of drug-induced receptor internalization in the HER2-positive SKBR3 breast cancer cell-line
Author(s): Fehling-Kaschek, Mirjam
Peckys, Diana B.
Kaschek, Daniel
Timmer, Jens
de Jonge, Niels
Language: English
Title: Scientific Reports
Volume: 9
Publisher/Platform: SpringerNature
Year of Publication: 2019
Free key words: Breast cancer
Computer modelling
Dynamical systems
Mechanisms of disease
Wide-field fluorescence microscopy
DDC notations: 530 Physics
Publikation type: Journal Article
Abstract: About 20% of breast cancer tumors over-express the HER2 receptor. Trastuzumab, an approved drug to treat this type of breast cancer, is a monoclonal antibody directly binding at the HER2 receptor and ultimately inhibiting cancer cell growth. The goal of our study was to understand the early impact of trastuzumab on HER2 internalization and recycling in the HER2-overexpressing breast cancer cell line SKBR3. To this end, fluorescence microscopy, monitoring the amount of HER2 expression in the plasma membrane, was combined with mathematical modeling to derive the flux of HER2 receptors from and to the membrane. We constructed a dynamic multi-compartment model based on ordinary differential equations. To account for cancer cell heterogeneity, a first, dynamic model was expanded to a second model including two distinct cell phenotypes, with implications for different conformational states of HER2, i.e. monomeric or homodimeric. Our mathematical model shows that the hypothesis of fast constitutive HER2 recycling back to the plasma membrane does not match the experimental data. It conclusively describes the experimental observation that trastuzumab induces sustained receptor internalization in cells with membrane ruffles. It is also concluded that for rare, non-ruffled (flat) cells, HER2 internalization occurs three orders of magnitude slower than for the bulk, ruffled cell population.
DOI of the first publication: 10.1038/s41598-019-49019-x
Link to this record: urn:nbn:de:bsz:291--ds-307715
hdl:20.500.11880/29039
http://dx.doi.org/10.22028/D291-30771
ISSN: 2045-2322
Date of registration: 22-Apr-2020
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Physik
Professorship: NT - Keiner Professur zugeordnet
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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