NR2F2 is a key downstream effector of NF1 loss in estorgen receptor positive breast cancer (ATAC-seq)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217415 | GEO | 2022/11/10
REPOSITORIES: GEO
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Project description:NF1 loss-of-function mutations are enriched in hormone receptor positive (HR+) metastatic breast cancer (MBC) and mediate endocrine therapy resistance. To identify therapeutic vulnerabilities in this context, we performed CRISPR/Cas9 screens in wildtype and NF1 knockout isogenic HR+ models and identified NR2F2, an orphan nuclear receptor, to be essential specifically in NF1 loss cells. The NR2F2 dependence was induced as a consequence of NR2F2 upregulation via the activation of the MAPK pathway in these cells. Enforced overexpression of NR2F2 was sufficient to confer endocrine therapy resistance in the absence of NF1 loss, while of NR2F2 knockout or knockdown could enhance the efficacy of endocrine therapies in NF1 WT and NF1 loss models. Mechanistically, our comprehensive multi-omics approaches revealed that NR2F2 modulates chromatin accessibility and regulates ER-dependent transcription through its interaction with ER, transcriptional coregulators and chromatin remodelers at chromatin. Specifically, increased NR2F2 in NF1 loss cells dramatically enhanced the association with transcriptional corepressors, which resulted in attenuation of chromatin accessibility and ER occupancy, and impaired ER transcriptional program. Our findings identify the nuclear receptor NR2F2 as a downstream effector of NF1 loss, and it is essential and potentially druggable mediator of endocrine therapy resistance. We performed gene expression profiling analysis using data obtained from RNA-seq of MCF7 sgNT, sgNF1, sgNR2F2 and double knockout (DKO) cells under different conditions.
2023-06-08 | GSE234074 | GEO
Project description:NF1 loss-of-function mutations are enriched in hormone receptor positive (HR+) metastatic breast cancer (MBC) and mediate endocrine therapy resistance. To identify therapeutic vulnerabilities in this context, we performed CRISPR/Cas9 screens in wildtype and NF1 knockout isogenic HR+ models and identified NR2F2, an orphan nuclear receptor, to be essential specifically in NF1 loss cells. The NR2F2 dependence was induced as a consequence of NR2F2 upregulation via the activation of the MAPK pathway in these cells. Enforced overexpression of NR2F2 was sufficient to confer endocrine therapy resistance in the absence of NF1 loss, while of NR2F2 knockout or knockdown could enhance the efficacy of endocrine therapies in NF1 WT and NF1 loss models. Mechanistically, our comprehensive multi-omics approaches revealed that NR2F2 modulates chromatin accessibility and regulates ER-dependent transcription through its interaction with ER, transcriptional coregulators and chromatin remodelers at chromatin. Specifically, increased NR2F2 in NF1 loss cells dramatically enhanced the association with transcriptional corepressors, which resulted in attenuation of chromatin accessibility and ER occupancy, and impaired ER transcriptional program. Our findings identify the nuclear receptor NR2F2 as a downstream effector of NF1 loss, and it is essential and potentially druggable mediator of endocrine therapy resistance. We performed ER chromatin binding profiling analysis using data obtained from ChIP-seq of MCF7 sgNT, sgNF1, sgNR2F2 and double knockout (DKO) cells under the conditions of full media, estrogen starvation and estrogen stimulation. We also performed NR2F chromatin binding profiling analysis using data obtained from ChIP-seq of MCF7 sgNT and sgNF1 cells under full media culture condition
2022-11-10 | GSE217416 | GEO
Project description:Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodelling complex, are the most common somatic alteration of the SWI/SNF complex across all cancers including oestrogen receptor positive (ER)+ breast cancer. We have recently reported that ARID1A inactivating mutations are present at a high frequency in advanced endocrine resistant ER+ breast cancer. In parallel, to identify mechanisms of resistance to endocrine therapy in breast cancer, we performed an epigenome CRISPR/CAS9 knockout screen that identified ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A knockout cells were found to be less responsive to endocrine therapy compared to intact ARID1A cells in vitro and in vivo. This set of observations in patients’ tumours and in unbiased CRISPR screens led us to explore the epigenetic mechanisms whereby loss of ARID1A may influence breast cancer progression and/or endocrine therapy resistance. ARID1A disruption in ER+ breast cancer cells led to widespread changes in chromatin accessibility converging on loss of the master transcription factors (TFs) that regulate gene expression programs critical for luminal lineage identity. Global transcriptome profiling of ARID1A knockout cell lines and patient samples harbouring ARID1A inactivating mutations revealed an enrichment for basal-like gene expression signatures. The state of increased cellular plasticity of luminal cells that acquire a basal-like phenotype upon ARID1A inactivation is enabled by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the major luminal-lineage determining transcription factors including ER, FOXA1, and GATA3. We also show that ARID1A regulates genome-wide ER-chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in the determination of breast luminal cell identity and endocrine therapeutic response in ER+ breast cancer.
2019-11-13 | GSE140186 | GEO
Project description:Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodelling complex, are the most common somatic alteration of the SWI/SNF complex across all cancers including oestrogen receptor positive (ER)+ breast cancer. We have recently reported that ARID1A inactivating mutations are present at a high frequency in advanced endocrine resistant ER+ breast cancer. In parallel, to identify mechanisms of resistance to endocrine therapy in breast cancer, we performed an epigenome CRISPR/CAS9 knockout screen that identified ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A knockout cells were found to be less responsive to endocrine therapy compared to intact ARID1A cells in vitro and in vivo. This set of observations in patients’ tumours and in unbiased CRISPR screens led us to explore the epigenetic mechanisms whereby loss of ARID1A may influence breast cancer progression and/or endocrine therapy resistance. ARID1A disruption in ER+ breast cancer cells led to widespread changes in chromatin accessibility converging on loss of the master transcription factors (TFs) that regulate gene expression programs critical for luminal lineage identity. Global transcriptome profiling of ARID1A knockout cell lines and patient samples harbouring ARID1A inactivating mutations revealed an enrichment for basal-like gene expression signatures. The state of increased cellular plasticity of luminal cells that acquire a basal-like phenotype upon ARID1A inactivation is enabled by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the major luminal-lineage determining transcription factors including ER, FOXA1, and GATA3. We also show that ARID1A regulates genome-wide ER-chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in the determination of breast luminal cell identity and endocrine therapeutic response in ER+ breast cancer.
2019-11-13 | GSE140185 | GEO
Project description:Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodelling complex, are the most common somatic alteration of the SWI/SNF complex across all cancers including oestrogen receptor positive (ER)+ breast cancer. We have recently reported that ARID1A inactivating mutations are present at a high frequency in advanced endocrine resistant ER+ breast cancer. In parallel, to identify mechanisms of resistance to endocrine therapy in breast cancer, we performed an epigenome CRISPR/CAS9 knockout screen that identified ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A knockout cells were found to be less responsive to endocrine therapy compared to intact ARID1A cells in vitro and in vivo. This set of observations in patients’ tumours and in unbiased CRISPR screens led us to explore the epigenetic mechanisms whereby loss of ARID1A may influence breast cancer progression and/or endocrine therapy resistance. ARID1A disruption in ER+ breast cancer cells led to widespread changes in chromatin accessibility converging on loss of the master transcription factors (TFs) that regulate gene expression programs critical for luminal lineage identity. Global transcriptome profiling of ARID1A knockout cell lines and patient samples harbouring ARID1A inactivating mutations revealed an enrichment for basal-like gene expression signatures. The state of increased cellular plasticity of luminal cells that acquire a basal-like phenotype upon ARID1A inactivation is enabled by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the major luminal-lineage determining transcription factors including ER, FOXA1, and GATA3. We also show that ARID1A regulates genome-wide ER-chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in the determination of breast luminal cell identity and endocrine therapeutic response in ER+ breast cancer.
2019-11-13 | GSE124227 | GEO
Project description:Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodelling complex, are the most common somatic alteration of the SWI/SNF complex across all cancers including oestrogen receptor positive (ER)+ breast cancer. We have recently reported that ARID1A inactivating mutations are present at a high frequency in advanced endocrine resistant ER+ breast cancer. In parallel, to identify mechanisms of resistance to endocrine therapy in breast cancer, we performed an epigenome CRISPR/CAS9 knockout screen that identified ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A knockout cells were found to be less responsive to endocrine therapy compared to intact ARID1A cells in vitro and in vivo. This set of observations in patients’ tumours and in unbiased CRISPR screens led us to explore the epigenetic mechanisms whereby loss of ARID1A may influence breast cancer progression and/or endocrine therapy resistance. ARID1A disruption in ER+ breast cancer cells led to widespread changes in chromatin accessibility converging on loss of the master transcription factors (TFs) that regulate gene expression programs critical for luminal lineage identity. Global transcriptome profiling of ARID1A knockout cell lines and patient samples harbouring ARID1A inactivating mutations revealed an enrichment for basal-like gene expression signatures. The state of increased cellular plasticity of luminal cells that acquire a basal-like phenotype upon ARID1A inactivation is enabled by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the major luminal-lineage determining transcription factors including ER, FOXA1, and GATA3. We also show that ARID1A regulates genome-wide ER-chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in the determination of breast luminal cell identity and endocrine therapeutic response in ER+ breast cancer.
2019-11-13 | GSE124225 | GEO
Project description:Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodelling complex, are the most common somatic alteration of the SWI/SNF complex across all cancers including oestrogen receptor positive (ER)+ breast cancer. We have recently reported that ARID1A inactivating mutations are present at a high frequency in advanced endocrine resistant ER+ breast cancer. In parallel, to identify mechanisms of resistance to endocrine therapy in breast cancer, we performed an epigenome CRISPR/CAS9 knockout screen that identified ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A knockout cells were found to be less responsive to endocrine therapy compared to intact ARID1A cells in vitro and in vivo. This set of observations in patients’ tumours and in unbiased CRISPR screens led us to explore the epigenetic mechanisms whereby loss of ARID1A may influence breast cancer progression and/or endocrine therapy resistance. ARID1A disruption in ER+ breast cancer cells led to widespread changes in chromatin accessibility converging on loss of the master transcription factors (TFs) that regulate gene expression programs critical for luminal lineage identity. Global transcriptome profiling of ARID1A knockout cell lines and patient samples harbouring ARID1A inactivating mutations revealed an enrichment for basal-like gene expression signatures. The state of increased cellular plasticity of luminal cells that acquire a basal-like phenotype upon ARID1A inactivation is enabled by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the major luminal-lineage determining transcription factors including ER, FOXA1, and GATA3. We also show that ARID1A regulates genome-wide ER-chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in the determination of breast luminal cell identity and endocrine therapeutic response in ER+ breast cancer.
2019-11-13 | GSE124224 | GEO
Project description:Estrogen receptor (ER) signaling–dependent cancer cell growth is one of the major features of ER-positive breast cancer (BC). Inhibition of ER function is a standard and effective treatment for ER-positive tumors; however, ~20% of patients with ER-positive BC experience early or late recurrence. In this study, we examined intertumor heterogeneity from an epigenetic perspective based on the hypothesis that the intrinsic difference in epigenetic states around ER signaling pathway underlies endocrine therapy resistance. We profiled chromatin accessibility data from 42 BC samples, including 35 ER-positive human epidermal growth factor receptor 2 (HER2)-negative and 7 triple-negative tumors, identifying a subgroup of ER-positive BCs with a distinctive chromatin accessibility pattern including reduced accessibility to ER-responsive elements (EREs). The same subgroup was also observed in The Cancer Genome Atlas BC cohort. Despite the reduced accessibility to EREs, the expression of ER and potential ER target genes were not decreased in these tumors. Our findings highlight the existence of a subset of ER-positive BCs with unchanged ER expression but reduced EREs accessibility that cannot be distinguished by conventional immunostaining for ER. Future studies should determine whether these tumors are associated with resistance to endocrine therapy.
2023-01-09 | GSE222116 | GEO
Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.485, 95% CI 0.265 to 0.889, p = 0.019; OS: HR 0.314, 95% CI 0.155 to 0.637, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.
2019-05-30 | GSE124647 | GEO
Project description:Endocrine therapy resistance invariably develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine resistant breast cancer cells and that the differential interactions are enriched for genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. Importantly, new 3D chromatin interactions often occur coincidently with hypermethylation and loss of ER binding. Additionally, alterations in active (A-type) and inactive (B-type) chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.
2019-12-11 | GSE118715 | GEO