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TRIM24 as therapeutic target in endocrine treatment resistant breast cancer

ABSTRACT: TRIM24 as therapeutic target in endocrine treatment resistant breast cancer

PROVIDER: PRJNA1034617 | ENA |

REPOSITORIES: ENA

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TRIM24 as therapeutic target in endocrine treatment resistant breast cancer

Project description:While ERα+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since in therapy-resistance tumors, ERα is still the main driver, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we describe TRIM24 as a key player 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 PROTAC targeting TRIM24, ERα-driven transcriptional output and growth was blocked, effectively treating not only endocrine-responsive cell lines, but also drug resistant derivates thereof as well as cell line models bearing activating ESR1 point mutations. Finally, using human tumor-derived organoid models, we could show efficacy of TRIM24 PROTAC in the endocrine responsive and resistant setting, with no response in ERα-negative organoids. Overall, our study positions TRIM24 as a central component for integrity and activity of the ERα transcriptional complex, with PROTAC-mediated perturbation of TRIM24 as promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer.

2025-08-01 | PXD046736 | Pride

TRIM24 as therapeutic target in endocrine treatment resistant breast cancer (ChIP-Seq)

Project description:While ERα+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since ERα is still the main driver in most therapy-resistance tumors, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we position TRIM24 as therapeutic target in endocrine resistance, in its role as key player 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 was blocked, effectively treating not only endocrine-responsive cell lines, but also drug resistant derivates thereof as well as cell line models bearing activating ESR1 point mutations. Finally, using human tumor-derived organoid models, we could show efficacy of TRIM24 degrader in the endocrine responsive and resistant setting. Overall, our study positions TRIM24 as a central component for integrity and activity of the ERα transcriptional complex, with degradation-mediated perturbation of TRIM24 as promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer.

2025-08-01 | GSE246794 | GEO

TRIM24 as therapeutic target in endocrine treatment resistant breast cancer (RNA-Seq)

2025-08-01 | GSE246793 | GEO

TRIM24 as therapeutic target in endocrine treatment resistant breast cancer (RNA-Seq)

Project description:TRIM24 as therapeutic target in endocrine treatment resistant breast cancer (RNA-Seq)

| PRJNA1034618 | ENA

TRIM24 as therapeutic target in endocrine treatment resistant breast cancer (ChIP-Seq)

Project description:TRIM24 as therapeutic target in endocrine treatment resistant breast cancer (ChIP-Seq)

| PRJNA1034619 | ENA

TRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer.

Project description: Not available

| S-EPMC12377727 | biostudies-literature

TRIM24 as therapeutic target in endocrine treatment resistant breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-08-01 | GSE246796 | GEO

Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer and nominates c-Met and TRIM24 as therapeutic targets

Project description:Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature revealed strong correlation with human MpBC tumors and MpBC xenograft (PDX) models. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC PDX tumorspheres revealed the therapeutic potential of targeting TRIM24. Altogether, global expression, single-cell immunophenotyping and mechanistic studies of tumors and MpBC PDX nominated TRIM24-activated c-MET/PI3K/mTOR pathways and TRIM24, which were validated as potential MpBC therapeutic targets.

2021-06-25 | GSE165407 | GEO

Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer and nominates potential therapeutic targets

Project description:Global profiling of tumor expression revealed increased RING-PHD-Bromodomain protein TRIM24 levels in numerous human cancers. Conditional over-expression of Trim24 was sufficient to drive murine mammary tumor development, 70% of which were ER, PR and HER2-negative carcinosarcomas with coexisting malignant epithelial and mesenchymal compartments, offering a unique model of human triple-negative, metaplastic breast cancer (MpBC). Both in vivo and in cellulo, TRIM24 induced EMT, repressing CDH1 and activating EMT factors. Whole exome sequencing of human MpBC tumors and Trim24-driven carcinosarcomas defined a TRIM24-like subclass of MpBC patients with worse overall and relapse-free survival. Among 40 MpBC patients, 43% had robust expression of TRIM24. These studies implicate TRIM24 as a potential biomarker and therapeutic target for a subset of MpBC.

2021-06-29 | GSE179036 | GEO

PARP-1 as a potential therapeutic target in ERα-positive endocrine therapy-resistant breast cancer

Project description:PARP-1 as a potential therapeutic target in ERα-positive endocrine therapy-resistant breast cancer

| PRJNA1164700 | ENA