HER4 Affects Sensitivity to Tamoxifen and Abemaciclib in Luminal Breast Cancer Cells and Restricts Tumor Growth in
Veruschka Albert1,2, Christina Bruss1,2, Deniz Tümen2,3
1Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93935 Regensburg, Germany.
Abstract:
The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7 in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients.
Insights
The HER4 receptor
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Estrogen receptor-positive (ER+) breast cancer treatment efficacy is uncertain.
- The role of the HER4 receptor in ER+ breast cancer growth and treatment response remains unclear.
- HER4's impact on endocrine therapy and targeted agents needs further elucidation.
Purpose of the Study:
- To investigate the functional impact of HER4 on ER+ breast cancer cell proliferation and treatment response.
- To elucidate the in vitro and in vivo mechanisms by which HER4 influences sensitivity to tamoxifen and abemaciclib.
- To assess the clinical relevance of HER4 expression in patients receiving abemaciclib therapy.
Main Methods:
- CRISPR/Cas9 gene editing to generate HER4 knockout breast cancer cell lines (MCF-7, T-47D, ZR-75-1).
- In vitro assessment of cell proliferation and drug response to tamoxifen, abemaciclib, AMG232, and NRG1.
- In vivo studies using humanized tumor mice (HTM) with HER4-wildtype and HER4-knockout xenografts to evaluate tumor growth and immunological effects.
- Analysis of clinical data correlating HER4 expression and mdm2 gene copy number with patient outcomes.
Main Results:
- HER4 knockout differentially modulated cellular responses to tamoxifen and abemaciclib, enhancing MCF-7 sensitivity.
- NRG1 treatment inhibited cell proliferation in HER4-expressing cells.
- HER4 knockout led to enhanced tumor growth in vivo, suggesting a tumor-suppressive role under specific conditions, associated with increased HER2 expression.
- Abemaciclib and tamoxifen effectively inhibited tumor growth independently of HER4 status.
- High HER4 expression or mdm2 gene copy gains correlated with reduced event-free survival in abemaciclib-treated patients.
Conclusions:
- HER4 status significantly influences the efficacy of tamoxifen and abemaciclib in ER+ breast cancer, with varying effects.
- HER4 may play a complex, context-dependent role in breast cancer growth and response to therapy.
- HER4 expression is a potential predictive biomarker for abemaciclib treatment outcomes in ER+ breast cancer patients.
