TRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer
Author(s)
Type
Journal Article
Abstract
While Estrogen receptor alpha (ERα)+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since ERα is still the main driver in most therapy-resistant tumors, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we position TRIM24 as a therapeutic target in endocrine resistance, given its role as a key component of the ERα transcriptional complex. TRIM24 interacts with ERα and other well-known ERα cofactors to facilitate ERα chromatin interactions and allows for maintenance of active histone marks including H3K23ac and H3K27ac. Consequently, genetic perturbation of TRIM24 abrogates ERα-driven transcriptional programs and reduces tumor cell proliferation capacity. Using a recently developed degrader targeting TRIM24, ERα-driven transcriptional output and growth were blocked, effectively treating not only endocrine-responsive cell lines but also drug-resistant derivatives thereof as well as cell line models bearing activating ESR1 point mutations. Finally, using human tumor-derived organoid models, we could show the efficacy of TRIM24 degrader in the endocrine-responsive and -resistant setting. Overall, our study positions TRIM24 as a central component for the integrity and activity of the ERα transcriptional complex, with degradation-mediated perturbation of TRIM24 as a promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer.
Date Issued
2025-08-19
Date Acceptance
2025-07-17
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2025, 122 (33)
ISSN
0027-8424
Publisher
National Academy of Sciences
Journal / Book Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
122
Issue
33
Copyright Statement
© 2025 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40815626
Subjects
ALIGNMENT
ALPHA
BINDING
breast cancer
DRUG
estrogen receptor alpha
ESTROGEN-RECEPTOR
FOXA1
heterobifunctional protein degrader
INHIBITORS
MEDIATOR
METASTATIC PROGRESSION
Multidisciplinary Sciences
REVEALS
Science & Technology
Science & Technology - Other Topics
therapy resistance breast cancer
TRIM24
Publication Status
Published
Coverage Spatial
United States
Article Number
2507571122
Date Publish Online
2025-08-15