Dataset Information

A functional interplay between ZNF217 and estrogen receptor alpha exists in luminal breast cancers.

ABSTRACT: We aimed at highlighting the role of ZNF217, a Krüppel-like finger protein, in Estrogen Receptor-? (ER?)-positive (ER+) and luminal breast cancers. Here we report for the first time that ZNF217 and ER? proteins bind to each other in both breast cancer cells and breast tumour samples, via the ER? hinge domain and the ZNF217 C-terminal domain. ZNF217 enhances the recruitment of ER? to its estrogen response elements (ERE) and the ER?-dependent transcription of the GREB1 estrogen-regulated gene. The prognostic power of ZNF217 mRNA expression levels is most discriminatory in breast cancers classified with a "good prognosis", particularly the Luminal-A subclass. A new immunohistochemistry ZNF217 index, based on nuclear and cytoplasmic ZNF217 staining, also allowed the identification of intermediate/poor relapse-free survivors in the Luminal-A subgroup. ZNF217 confers tamoxifen resistance in ER+ breast cancer cells and is a predictor of relapse under endocrine therapy in patients with ER+ breast cancer. ZNF217 thus allows the re-stratification of patients with ER+ breast cancers considered as cancers with good prognosis where no other biomarkers are currently available and widely used. Here we propose a model in ER+ breast cancer where ZNF217-driven aggressiveness incorporates ZNF217 as a positive enhancer of ER? direct genomic activity and where ZNF217 possesses its highest discriminatory prognostic value.

SUBMITTER: Nguyen NT

PROVIDER: S-EPMC5528595 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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A functional interplay between ZNF217 and estrogen receptor alpha exists in luminal breast cancers.

Nguyen Nhan T NT Vendrell Julie A JA Poulard Coralie C Győrffy Balázs B Goddard-Léon Sophie S Bièche Ivan I Corbo Laura L Le Romancer Muriel M Bachelot Thomas T Treilleux Isabelle I Cohen Pascale A PA

Molecular oncology 20140610 8

We aimed at highlighting the role of ZNF217, a Krüppel-like finger protein, in Estrogen Receptor-α (ERα)-positive (ER+) and luminal breast cancers. Here we report for the first time that ZNF217 and ERα proteins bind to each other in both breast cancer cells and breast tumour samples, via the ERα hinge domain and the ZNF217 C-terminal domain. ZNF217 enhances the recruitment of ERα to its estrogen response elements (ERE) and the ERα-dependent transcription of the GREB1 estrogen-regulated gene. The ...[more]

PMID: 24973012

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Project description:BACKGROUND: Estrogen receptors alpha (ER?) and beta (ER?) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ER? being able to modulate the effects of ER? on gene transcription and cell proliferation. ER? is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ER? in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. RESULTS: Expression of full-length ER? in hormone-responsive, ER?-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ER? and 6024 ER? binding sites in estrogen-stimulated cells, comprising sites occupied by either ER?, ER? or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ER?+ vs ER?- cells, 424 showed one or more ER? site within 10 kb. These putative primary ER? target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ER? binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. CONCLUSIONS: Results indicate that the vast majority of the genomic targets of ER? can bind also ER?, suggesting that the overall action of ER? on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell.

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A functional interplay between ZNF217 and estrogen receptor alpha exists in luminal breast cancers.

Publications

A functional interplay between ZNF217 and estrogen receptor alpha exists in luminal breast cancers.

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