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APOBEC3B facilitates a functional and necessary link between oestrogen receptor mediated transcription and DNA repair

ABSTRACT: Oestrogen receptor-α (ER) is the principal transcription factor in the majority of breast cancers, driving expression of genes that control cell growth and endocrine response. Understanding the mechanisms of ER action is crucial for improving response to endocrine treatments. Recent studies show that cytosine deaminase (CD) activity is an important source of cancer mutations. In particular, APOBEC3B (A3B) promotes mutagenesis in breast cancer cells1. Our analysis of breast cancer expression datasets showed that A3B expression predicts for poor survival in ER-positive, but not in ER-negative patients, indicative of a link with ER activity. Chromatin immunoprecipitation coupled to deep sequencing (ChIP-seq) used to map global A3B binding sites showed a remarkable oestrogen-stimulated recruitment of A3B to ER binding sites. Functionally, A3B was critical for ER transcriptional activity and regulated breast cancer cell proliferation. We show that A3B regulates ER transcription by promoting cytosine deamination and activation of DNA strand break repair at ER binding regions. We propose that cytosine deamination and DNA strand break generation by A3B facilitates gene expression by aiding chromatin remodeling at ER target genes. Our findings also suggest a mechanism by which subversion of transcription factor mediated recruitment of cytosine deaminases promotes cancer mutations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56979 | GEO | 2015/09/30

SECONDARY ACCESSION(S): PRJNA245103

REPOSITORIES: GEO

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APOBEC3B facilitates a functional and necessary link between estrogen receptor mediated transcription and DNA repair

Project description:Oestrogen receptor-α (ER) is the principal transcription factor in the majority of breast cancers, driving expression of genes that control cell growth and endocrine response. Understanding the mechanisms of ER action is crucial for improving response to endocrine treatments. Recent studies show that cytosine deaminase (CD) activity is an important source of cancer mutations. In particular, APOBEC3B (A3B) promotes mutagenesis in breast cancer cells1. Our analysis of breast cancer expression datasets showed that A3B expression predicts for poor survival in ER-positive, but not in ER-negative patients, indicative of a link with ER activity. Chromatin immunoprecipitation coupled to deep sequencing (ChIP-seq) used to map global A3B binding sites showed a remarkable oestrogen-stimulated recruitment of A3B to ER binding sites. Functionally, A3B was critical for ER transcriptional activity and regulated breast cancer cell proliferation. We show that A3B regulates ER transcription by promoting cytosine deamination and activation of DNA strand break repair at ER binding regions. We propose that cytosine deamination and DNA strand break generation by A3B facilitates gene expression by aiding chromatin remodeling at ER target genes. Our findings also suggest a mechanism by which subversion of transcription factor mediated recruitment of cytosine deaminases promotes cancer mutations. Hormone-depleted MCF-7 breast cancer cell line was treated with estrogen (100 nM), H2O2 (10 mM) or vehicle for 45 minutes. H2AX ChIP-seq was performed using Illumina methodology.

2015-09-07 | E-GEOD-57426 | biostudies-arrayexpress

APOBEC3B facilitates a functional and necessary link between estrogen receptor mediated transcription and DNA repair

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The RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B

Project description:Mutations in cancer are due in part to DNA cytosine deamination by APOBEC3B (A3B). While low in healthy tissues, A3B expression and activity are elevated in tumors and further increase in metastases. However, molecular mechanisms responsible for A3B transcriptional regulation are poorly understood. Here, we address whether the RB/E2F pathway, which is often dysregulated in breast cancer, is a molecular trigger of A3B overexpression. First, an A3B promoter-driven luciferase reporter was used to demonstrate reporter activation by disruption of only one out of five predicted E2F binding sites. Second, A3B-luciferase reporter activation was also triggered by expressing the BK polyomavirus T-antigen, which inactivates RB and thereby alleviates repression of E2F regulated genes. Importantly, A3B-luciferase reporter induction by BK polyomavirus T-antigen could not be further increased by mutating the functional E2F binding site. Third, both CRISPR disruption and targeted base substitutions in the endogenous E2F binding site caused strong A3B upregulation and confirmed importance of this regulatory element. Fourth, proteomics experiments showed that members of the DREAM and PRC1.6-complexes including multiple E2F family members are able to bind to wild-type but not E2F mutant promoter sequences. Finally, a combination of genetic and biochemical studies implicated E2F4 and E2F6 in endogenous A3B gene repression. Altogether, our studies demonstrate that A3B expression is suppressed in normal cells by the RB/E2F axis and that viral or mutational disruption of this pathway causes overexpression of this DNA deaminase in cancer and contributes mutational fuel to tumor evolution.

2020-10-19 | PXD020473 | Pride

Dynamic methylation and expression of alternative promoters for oestrogen receptor alpha in cell line models of fulvestrant resistance

Project description:Oestrogen receptor alpha (ER, gene symbol ESR1) is the most important prognostic and treatment-predictive biomarker in breast cancer. Drugs targeting oestrogen and the ER for endocrine therapy of breast cancer include aromatase inhibitors, the selective ER modulator tamoxifen and the selective ER degrader fulvestrant. Tumours can develop resistance to endocrine therapy through several mechanisms, which is often linked to altered expression of the ER. To investigate the role of promoter methylation in regulation of ER expression, we used bisulfite sequencing to measure methylation at CpG sites in alternative ER promoter regions for six cell line models of fulvestrant resistance. Both CpG methylation and expression of alternative first exons changed dynamically with striking differences between cell lines that had stable or unstable resistance upon fulvestrant withdrawal. Methylation at some CpG sites was strongly negatively correlated with expression of specific first exons. In a breast tumour cohort, higher relative expression of upstream alternative first exons was associated with worse prognosis in post-menopausal women with ER-positive tumours who received endocrine therapy.

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ARID1A is a critical regulator of luminal identity and therapeutic response in oestrogen receptor-positive breast cancer (ChIP-Seq)

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.

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ARID1A is a critical regulator of luminal identity and therapeutic response in oestrogen receptor-positive breast cancer (ATAC-Seq)

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