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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246793 | GEO | 2025/08/01

REPOSITORIES: GEO

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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

Estrogen Receptor alpha and Histone Lysine Methyltransferase DOT1L chromatin bound interactome

Project description:Estrogen Receptor alpha (ERα) is a ligand-inducible transcription factor that mediates estrogen signaling in hormone-responsive breast cancer (BC) and is the primary target of specific anticancer therapies. Although ERα blockade with these drugs is effective, the development of a resistance to treatment represents the key problem in clinical management of patients affected by this disease. Understanding the molecular mechanisms underlying ERα action in BC cells may help the identification of new therapeutic targets for more effective pharmacological treatment of endocrine therapy-resistant tumors. We recently discovered the epigenetic enzyme DOT1L (DOT1 Like Histone Lysine Methyltransferase) as a novel nuclear partner of ERα in BC cells. To investigate the involvement of DOT1L in mediating ERα actions in hormone-responsive and endocrine-resistant BC, physical and functional interaction between these two molecules on chromatin was mapped by Chromatin Immunoprecipitation coupled to Mass Spectrometry (ChIP-MS).

2019-02-09 | PXD010314 | Pride

DOT1 Like Histone Lysine Methyltransferase (DOT1L) and Menin 1 (MEN1) interaction proteomics in breast cancer cell nuclei

Project description:Estrogen Receptor alpha (ERα) is a ligand-inducible transcription factor that mediates estrogen signaling in hormone-responsive breast cancer (BC) and is the primary target of specific anticancer therapies that although effective can generate resistance phenomena that represents a crucial problem in clinical management of patients affected by this disease. DOT1 Like Histone Lysine Methyltransferase (DOT1L) and Menin 1 (MEN1) have been identified as functional component of the ERα mechanism of action. To investigate the involvement of DOT1L and MEN1 in mediating ERα actions in hormone-responsive and endocrine-resistant BC, interaction proteomics was applied to map the DOT1l and MEN1 nuclear interacting partners in MCF7 breast cancer cell nuclei in order to the identifiy new possible therapeutic targets for a more effective pharmacological treatment of endocrine therapy-resistant tumors.

2022-08-12 | PXD026864 | Pride

Dynamic changes during adaptation to estrogen deprivation in MCF7 cell line

Project description:Endocrine therapies targeting the proliferative effect of 17β-estradiol (17βE2) through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through a molecular mechanism that is not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors (AIs) in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were influenced by transcription factors known to be involved in acquired resistance or cell proliferation (e.g. IRF1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and recurrence after tamoxifen treatment. This study proposes a mechanism for acquired resistance to estrogen deprivation that is coordinated across biological levels and independent of canonical ERα function. LTED (long term estrogen deprived) cell line was generated from MCF-7 cells by long-term culture under estrogen deprivated conditions. And RNA samples were obtained after 3, 15, 30, 90, 120, 150 and 180 days.

2010-09-01 | E-GEOD-20361 | biostudies-arrayexpress

Dynamic changes during adaptation to estrogen deprivation in MCF7 cell line

2010-09-01 | GSE20361 | GEO

Growth Factor Stimulation Induces a Distinct ERα Cistrome Underlying Breast Cancer Endocrine Resistance

Project description:Estrogen receptor alpha (ERα) expression in breast cancer is predictive of response to endocrine therapy, however resistance is common in ERα-positive tumors that over-express the growth factor receptor ERBB2. Even in the absence of estrogen, ERα can be activated by growth factors including the epidermal growth factor (EGF). EGF induces a transcriptional program distinct from estrogen, however the mechanism of the stimulus-specific response is unknown. Here we show that the EGF-induced ERα genomic targets, its cistrome, are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1. The EGF-induced ERα cistrome specifically regulates genes found over-expressed in ERBB2-positive human breast cancers. This provides a potential molecular explanation for the endocrine therapy resistance seen in ERα-positive breast cancers that over-express ERBB2. These results suggest a central role for ERα in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ERα as opposed to blocking its estrogen responsiveness alone.

2010-12-29 | GSE26081 | GEO

Exploring the Spatial Landscape of the Estrogen Receptor Proximal Proteome With Antibody-Based Proximity Labeling

Project description:Estrogen Receptor-α (ERα) plays a crucial role in breast cancer, driving the transcription of genes involved in tumor progression. The ERα function is dependent on multiple protein-protein interactions (PPIs). As a result of rapid tumor adaptation, these are often altered by drug treatments and acquired mutations. Although elucidating how ERα PPIs evolve in response to therapies is critical to fully uncover drug resistance, capturing transient interactions in their subcellular context remains a major challenge. In this study, we used Biotinylation by Antibody Recognition (BAR) coupled with mass spectrometry to investigate the ERα proximal proteome and its perturbations associated with endocrine resistance.

2024-05-09 | PXD043294 | Pride

RET Ligands Mediate Endocrine Sensitivity via a Bi-stable Feedback Loop with ERα

Project description:The molecular mechanisms of endocrine resistance in breast cancer remain poorly understood. Here we used PRO-seq to map the location of hundreds of genes and thousands of distal enhancers whose activities differ between endocrine sensitive and resistant MCF-7 cells. Our genome-wide screen identified a 16-fold transcriptional increase in glial-cell line derived neurotrophic factor (GDNF), a RET tyrosine kinase receptor ligand, which is both necessary and sufficient for resistance in MCF-7 cells. GDNF causes endocrine resistance by switching the active state of a bi-stable feedback loop from ERα signaling to GDNF-RET signaling. To catalyze this switch, we found that GDNF directly downregulates ERα transcription and activates the transcription factor EGR1, which, in turn, induces GDNF expression. Remarkably, both MCF-7 cells and ER+ primary tumors appear poised for endocrine resistance via the RET signaling pathway, but lack robust RET ligand expression and only develop resistance upon expression of GDNF or other RET ligands.

2018-02-22 | GSE93229 | GEO

Functional effect of DOT1L pharmacological inhibition in ERα-positive Ovarian Cancer cells

Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.

2019-11-04 | E-MTAB-8198 | biostudies-arrayexpress

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