Mathematical modeling of drug-induced receptor internalization in the HER2-positive SKBR3 breast cancer cell-line
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Updated: Jan 20, 2026
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Mirjam Fehling-Kaschek1, Diana B Peckys2, Daniel Kaschek1
1Institute of Physics, Freiburg University, 79104, Freiburg, Germany.
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.
Insights
Trastuzumab treatment causes sustained HER2 receptor internalization in breast cancer cells with membrane ruffles. Mathematical modeling revealed slower HER2 internalization in rare, non-ruffled cells, impacting treatment response.
Area of Science:
- Oncology
- Biophysics
- Mathematical Biology
Background:
- Approximately 20% of breast cancers over-express the Human Epidermal growth factor Receptor 2 (HER2).
- Trastuzumab, a HER2-targeting monoclonal antibody, is a standard treatment for HER2-positive breast cancer.
- Understanding HER2 receptor dynamics is crucial for optimizing cancer therapy.
Purpose of the Study:
- To investigate the early effects of Trastuzumab on HER2 receptor internalization and recycling.
- To model HER2 dynamics in the SKBR3 breast cancer cell line using mathematical approaches.
- To explore the role of cell heterogeneity in HER2 receptor trafficking.
Main Methods:
- Utilized fluorescence microscopy to quantify HER2 expression on the plasma membrane.
- Developed a dynamic multi-compartment mathematical model based on ordinary differential equations.
- Incorporated cell heterogeneity by modeling two distinct cell phenotypes (ruffled and non-ruffled).
Main Results:
- The mathematical model demonstrated that rapid, constitutive HER2 recycling does not align with experimental observations.
- Trastuzumab was shown to induce sustained HER2 receptor internalization in cells exhibiting membrane ruffles.
- HER2 internalization was found to be three orders of magnitude slower in rare, non-ruffled cells compared to the majority of ruffled cells.
Conclusions:
- The study provides a quantitative description of Trastuzumab's impact on HER2 trafficking dynamics.
- Cellular heterogeneity, specifically the presence of membrane ruffles, significantly influences HER2 internalization rates.
- These findings offer insights into the mechanisms underlying Trastuzumab efficacy and resistance in HER2-positive breast cancer.
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