biostudies-literaturePadrao NBreast Cancer Ireland (BCI)Cancer Research UKEuropean Research CouncilBreast Cancer NowKWF Kankerbestrijding (DCS)ZonMwResearch Irelande2507571122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12377727biostudies-literatureUnknown122(33)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 <i>ESR1</i> 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.Proceedings of the National Academy of Sciences of the United States of AmericaTRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer.PMC1237772720/FFP-P/859781359923/SPP/1178318239A012019AugSF1310016.156.4012021JulyPCC146019/FFP/64432014MayPR234C37/A187849171640Vareslija DPadrao NSiefert JSeverson TMBuluwela LLuzietti LGregoricchio SDonaldson Collier MBossi DZwart WEickhoff NDong JAli STheurillat JPYoung LCalcinotto AfalseTRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer.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 <i>ESR1</i> 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.2025-01-01T00:00:00Z2025 Aug2026-05-10T04:21:59.365Z2026-04-08T01:29:08.821ZS-EPMC123777274081562610.1073/pnas.2507571122