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Updated: Jun 23, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
BET-directed PROTACs in triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-436
Maryana Teufelsbauer1, Sandra Stickler2, Marie-Therese Eggerstorfer2
1Clinics of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria.
Purpose:
This study aims to find whether the proliferation and migration of triple negative breast cancer (TNBC) cell lines can be reduced by treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 and BET protein targeting chimeras (PROTACs) ARV-771 and MZ1.
Methods:
Cytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression.
Results:
JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors.
Conclusion:
The degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC.
Insights
Bromodomain and extra-terminal domain (BET) inhibitors and PROTACs significantly reduced triple negative breast cancer (TNBC) cell proliferation and migration. BET protein degradation via PROTACs shows promise for future TNBC therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) remains a challenging malignancy with limited targeted therapies.
- Bromodomain and extra-terminal domain (BET) proteins are epigenetic regulators implicated in cancer cell proliferation and migration.
- BET protein targeting chimeras (PROTACs) offer a novel therapeutic strategy by inducing targeted protein degradation.
Purpose of the Study:
- To investigate the efficacy of the BET inhibitor JQ1 and BET-directed PROTACs (ARV-771, MZ1) in reducing TNBC cell proliferation and migration.
- To evaluate the impact of these agents on protein expression in TNBC cell lines.
- To explore the potential of BET inhibition and degradation as a therapeutic approach for TNBC.
Main Methods:
- Cytotoxicity assays were performed to assess cell viability.
- Scratch migration assays were utilized to evaluate cell migration.
- Western blot proteome profiler arrays were employed to analyze protein expression changes.
Main Results:
- JQ1, ARV-771, and MZ1 significantly inhibited proliferation and migration in KRAS G13D-mutated MDA-MB-231 TNBC cells.
- PROTACs suppressed ERBB2/HER2, 3, and 4 expression in MDA-MB-231 cells, rendering them sensitive to HER2 inhibitors.
- In MDA-MB-436 cells, PROTACs primarily affected cytokine and receptor expression.
Conclusions:
- Degradation of BET proteins by PROTACs demonstrated significant anti-proliferative effects in TNBC cells.
- KRAS-mutated TNBC cells with low HER2 expression have a poorer prognosis and may benefit from BET-targeted therapies.
- PROTAC technology is emerging as a promising therapeutic strategy for future TNBC treatment, with oral agents entering clinical trials.
