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ZNF217 is an oncogene that promotes a basal phenotype and expansion of a progenitor cell population during breast cancer progression

ABSTRACT: Amplification of 20q13 occurs in 20-30% of primary human breast cancers and correlates with poor prognosis. The transcription factor ZNF217 is a candidate oncogene in 20q13. Patients with breast tumors expressing high ZNF217 had reduced survival and increased resistance to chemotherapy. Inducible Znf217 expression in the mammary epithelium of our transgenic mouse resulted in premalignant and invasive lesions. Znf217 overexpression in a mouse luminal breast cancer model generated primary tumors with heterogeneous epithelial and progenitor cell marker expression and promoted metastasis. The AKT inhibitor triciribine inhibited growth and restored sensitivity to a cytotoxic drug in cells expressing high ZNF217. Triciribine reduced tumor burden in vivo, suggesting that ZNF217 may be a novel drug target. Total RNA was isolated from samples overexpressing ZNF217 (4 NMuMG). RNA was also harvested from each cell line expressing a vector control to use as a reference for each microarray sample analyzed. Total RNA was hybridized to mouse MEEBO arrays as described (http://www.microarray.org/sfgf/meebo.do). Samples were verified to have strong overexpression of ZNF217 by qRT-PCR or Western analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Laurie Littlepage

PROVIDER: E-GEOD-38047 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression

Project description:The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20-30% of primary human breast cancers and that correlates with poor prognosis. We show Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We demonstrate that the nucleoside analog triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance, and inhibits signaling events (e.g., P-AKT, P-MAPK) in vivo. Our data suggest ZNF217 is a biomarker of poor prognosis and a therapeutic target in breast cancer patients, and triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Since ZNF217 is amplified in numerous cancers, these results have implications for other cancers. Total RNA was isolated from samples overexpressing ZNF217 (3 Primary and 5 SCp2). RNA was also harvested from each cell line expressing a vector control to use as a reference for each microarray sample analyzed. Total RNA was hybridized to mouse MEEBO arrays as described (http://www.microarray.org/sfgf/meebo.do). Samples were verified to have strong overexpression of ZNF217 by qRT-PCR or Western analysis.

2012-05-17 | E-GEOD-24727 | biostudies-arrayexpress

ZNF217 is an oncogene that promotes a basal phenotype and expansion of a progenitor cell population during breast cancer progression

Project description:Amplification of 20q13 occurs in 20-30% of primary human breast cancers and correlates with poor prognosis. The transcription factor ZNF217 is a candidate oncogene in 20q13. Patients with breast tumors expressing high ZNF217 had reduced survival and increased resistance to chemotherapy. Inducible Znf217 expression in the mammary epithelium of our transgenic mouse resulted in premalignant and invasive lesions. Znf217 overexpression in a mouse luminal breast cancer model generated primary tumors with heterogeneous epithelial and progenitor cell marker expression and promoted metastasis. The AKT inhibitor triciribine inhibited growth and restored sensitivity to a cytotoxic drug in cells expressing high ZNF217. Triciribine reduced tumor burden in vivo, suggesting that ZNF217 may be a novel drug target.

2015-05-18 | GSE38047 | GEO

The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression

2012-05-18 | GSE24727 | GEO

Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with Eralpha

Project description:Background: The ZNF217 gene, encoding a C2H2 zinc finger protein, is located at 20q13 and found amplified and overexpressed in greater than 20% of breast tumors. Current studies indicate ZNF217 drives tumorigenesis, yet the regulatory mechanisms of ZNF217 are largely unknown. Because ZNF217 associates with chromatin modifying enzymes, we postulate that ZNF217 functions to regulate specific gene signaling networks. Here, we present a large-scale functional genomic analysis of ZNF217, which provides insights into the regulatory role of ZNF217 in MCF7 breast cancer cells. Results: ChIP-seq analysis reveals that the majority of ZNF217 binding sites are located at distal regulatory regions associated with the chromatin marks H3K27ac and H3K4me1. Analysis of ChIPseq transcription factor binding sites shows clustering of ZNF217 with FOXA1, GATA3 and ERalpha binding sites, supported by the enrichment of corresponding motifs for the ERalpha-associated cisregulatory sequences. ERalpha expression highly correlates with ZNF217 in lysates from breast tumors (n=15), and ERalpha co-precipitates ZNF217 and its binding partner CtBP2 from nuclear extracts. Transcriptome profiling following ZNF217 depletion identifies differentially expressed genes co-bound by ZNF217 and ERalpha; gene ontology suggests a role for ZNF217-ERalpha in expression programs associated with ER+ breast cancer studies found in the Molecular Signature Database. Data-mining of expression data from breast cancer patients correlates ZNF217 with reduced overall survival in multiple subtypes. Conclusions: Our genome-wide ZNF217 data suggests a functional role for ZNF217 at ERalpha target genes. Future studies will investigate whether ZNF217 expression contributes to aberrant ERalpha regulatory events in ER+ breast cancer and hormone resistance

2014-06-15 | GSE58326 | GEO

Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with Eralpha

2014-06-15 | E-GEOD-58326 | biostudies-arrayexpress

Transcriptional profiles on different yeast strain mutants

Project description:Transcriptional profiles on different yeast strain mutants (DEgd2/1, DEgd2/Btt1)were identified by microarray analysis comparing total mutant RNA vs wild type RNA. Set of arrays that are part of repeated experiments

2013-04-05 | E-GEOD-45796 | biostudies-arrayexpress

Defining the specificity of cotranslationally acting chaperones by systematic analysis of mRNAs associated with ribosome-nascent chain complexes.

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-04-05 | E-GEOD-45798 | biostudies-arrayexpress

RNA coimmunoprecipitations

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2013-04-05 | E-GEOD-45794 | biostudies-arrayexpress

RNA messengers translated at the ER membrane

Project description:In order to identify what RNA messengers are being translated at the ER membrane, membrane-associated polysomes were separated from free polysomes by subcellular fractionation of WT and delta-egd1/delta-egd2 yeast strains and associated RNA was isolated and then identified by microarray analysis. Set of arrays that are part of repeated experiments

2013-04-05 | E-GEOD-45795 | biostudies-arrayexpress

Identification of genes directly regulated by the oncogene ZNF217 using ChIP-chip assays

Project description:It has been proposed that ZNF217, which is amplified at 20q13 in various tumors, plays a key role during neoplastic transformation. ZNF217 has been purified in complexes that contain repressor proteins such as CtBP2, suggesting that it acts as a transcriptional repressor. However, the function of ZNF217 has not been well characterized due to a lack of known target genes. Using a global ChIP-chip approach, we have identified thousands of ZNF217 binding sites in three tumor cell lines (MCF7, SW480, and Ntera2). Further analysis of ZNF217 in Ntera2 cells has shown that many promoters are bound by ZNF217 and CtBP2, and that a subset of these promoters are activated upon removal of ZNF217. Thus, our in vivo studies corroborate the in vitro biochemical analyses of ZNF217-containing complexes and support the hypothesis that ZNF217 functions as transcriptional repressor. Gene ontology analysis shows that ZNF217 targets in Ntera2 cells are involved in organ development, suggesting that one function of ZNF217 may be to repress differentiation. Accordingly, we show that differentiation of Ntera2 cells with retinoic acid leads to downregulation of ZNF217. Our identification of thousands of ZNF217 target genes will enable further studies of the consequences of aberrant expression of ZNF217 during neoplastic transformation. Keywords: ChIP-chip

2007-01-25 | GSE6624 | GEO

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