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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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HOXB7 is an ERÎ± cofactor in the activation of HER2 and multiple ER target genes leading to endocrine resistance

ABSTRACT: Why breast cancers become resistant to tamoxifen despite continued expression of the estrogen receptor alpha (ERÎ±) and what factors are responsible for high HER2 expression in these tumors remains an enigma. HOXB7 ChIP analysis followed by validation showed that HOXB7 physically interacts with ERÎ±, and that the HOXB7-ERÎ± complex enhances transcription of many ERÎ± target genes including HER2. Investigating strategies for controlling HOXB7, our studies revealed that MYC, stabilized via phosphorylation mediated by EGFR-HER2 signaling, inhibits transcription of miRNA-196a, a HOXB7 repressor. This leads to increased expression of HOXB7, ER-target genes and HER2. Repressing MYC using small molecule inhibitors reverses these events, and causes regression of breast cancer xenografts. The MYC-HOXB7-HER2 signaling pathway is eminently targetable in endocrine-resistant breast cancer. MCF7 cell lines stably transduced with either vector control of HOXB7. Array ran in duplicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Saraswati Sukumar

PROVIDER: E-GEOD-63607 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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HOXB7 is an ERα cofactor in the activation of HER2 and multiple ER target genes leading to endocrine resistance

Project description:Why breast cancers become resistant to tamoxifen despite continued expression of the estrogen receptor alpha (ERα) and what factors are responsible for high HER2 expression in these tumors remains an enigma. HOXB7 ChIP analysis followed by validation showed that HOXB7 physically interacts with ERα, and that the HOXB7-ERα complex enhances transcription of many ERα target genes including HER2. Investigating strategies for controlling HOXB7, our studies revealed that MYC, stabilized via phosphorylation mediated by EGFR-HER2 signaling, inhibits transcription of miRNA-196a, a HOXB7 repressor. This leads to increased expression of HOXB7, ER-target genes and HER2. Repressing MYC using small molecule inhibitors reverses these events, and causes regression of breast cancer xenografts. The MYC-HOXB7-HER2 signaling pathway is eminently targetable in endocrine-resistant breast cancer.

2014-11-25 | GSE63607 | GEO

The effect of miRNA overexpression on gene expression profile of MCF-7 cells

Project description:To identify microRNAs impacting estrogen receptor ERÎ± expression in breast cancer, we have screened ER-positive breast cancer cells with a library of pre-miRs, and systematically monitored the ERÎ± expression by protein lysate microarrays. There was a significant enrichment of the in silico predicted ERÎ± targeting microRNAs among the hits. The most potent pre-miRs miR-18a/b, miR-193b, miR-206, and miR-302c, were confirmed to directly target ERÎ± and to repress estrogen-responsive genes. The effect of miRNA overexpression on gene expression profile of MCF-7 cells was studied. Furthermore, miR-18a and miR-18b showed increased expression in ERÎ±-negative as compared to ERÎ±-positive clinical tumors. In summary, we present systematic and direct functional and correlative clinical evidence on microRNAs inhibiting ERÎ± signaling in breast cancer. MCF-7 cells (300Â 000 per well on 6-well plates) were transfected with an siRNA for ERÎ± or with Ambion pre-miRâ?¢ constructs for miR-18a, miR-193b, miR-206, miR-302c, or pre-miR negative control #1 (scrambled pre-miR) at 20 nM, and incubated for 24h.

2010-04-09 | E-GEOD-14847 | biostudies-arrayexpress

RNA-seq of the human breast cancer ERÎ±-suppressed MCF-7(MCF-7/SP10+) cells and of their internal control MCF-7 (MCF-7/C) cells

Project description:Estrogens receptor a (ERÎ±) is essential for breast tumors,since about seventy percent of breast cancers are detected as ERÎ± positive.Recent studies suggest that ERÎ± is related with the epithelial cell morphology. Recently, it has demonstrated that the suppression of ERÎ± induced epithelial-mesenchymal transition (EMT) in the MCF-7 breast cacner cells. Interestingly, the loss of ERa resulted in strong differences on the gene expression profile of a variety of genes. Therefore, the aim of the RNA-seq is to elucidate the effect of the silencing of ERÎ± on the mRNA levels of a larger variety of genes, thus revealing possible target genes which may be implicated on the aggressive phenotype and behavior of the ERÎ±-suppresed MCF-7/SP10+ breast cancer cells. For this reason total RNA from both MCF-7/SP10+ cells and of their internal control MCF-7/C cells was extracted in 3 biological replicates and 3 technical replicates.

2018-10-22 | E-MTAB-5537 | biostudies-arrayexpress

Genomic Collaboration of Estrogen Receptor-Î± and ERK2 in Regulating Gene and Proliferation Programs

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2011-01-10 | E-GEOD-24592 | biostudies-arrayexpress

Activator protein-2Î³ is a critical determinant of estrogen receptor interactome formation and gene transcription in breast cancer [expression]

Project description:Estrogen receptor Î± (ERÎ±) is key player in the progression of breast cancer. ERÎ± binds to DNA and mediates long-range chromatin interactions throughout the genome, but the underlying mechanism in this process is unclear. Here, we show that AP-2 motifs are highly enriched in the ERÎ± binding sites (ERBS) identified from the recent ChIA-PET of ERÎ±. More importantly, we demonstrate that AP-2Î³ (also known as TFAP2C), a member of the AP-2 family which has been implicated in breast cancer oncogenesis, is recruited to chromatin in a ligand-independent manner and co-localized with ERÎ± binding events. Furthermore, pertubation of AP-2Î³ expression disrupts ERÎ± DNA binding, long-range chromatin interactions, and gene transcription. Using ChIP-seq, we show that AP-2Î³ and ERÎ± binding occurs in close proximity on a genome-wide scale. The majority of these shared genomic regions are also occupied by the pioneer factor, FoxA1. AP-2Î³ is required for efficient FoxA1 binding and vice versa. Finally, we show that most ERBS associated with long-range chromatin interactions are co-localized with both AP-2Î³ and FoxA1. Together, our results suggest AP-2Î³ is an essential factor in ERÎ±-mediated transcription, primarily working together with FoxA1 to facilitate ERÎ± binding and long-range chromatin interactions. Gene expression profiling of negative control (NC) and AP-2Î³ siRNA transfected MCF-7, with and without E2 (estradiol) stimulation using microarray.

2011-06-02 | E-GEOD-26740 | biostudies-arrayexpress

A Myc transcriptional program that is independent of EMT drives a poor prognosis tumor-propagating phenotype in HER2+ breast cancer

Project description:The HER2 (ERBB2) and MYC genes are commonly amplified genes in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self renewal and tumour propagating capability of cells transformed with Her2 and c-Myc. Co-expression of both oncogenes in cultured cells led to a pronounced activation of a c-Myc transcriptional signature and acquisition of a self renewing phenotype independent of an EMT programme or regulation of cancer stem cell markers. We show that HER2 and c-MYC are frequently co-amplified in a clinical breast cancer cohort and that co-amplification is strongly associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in patients receiving adjuvant chemotherapy (but not targeted anti-HER2 therapy), MYC amplification is associated with a poor outcome in HER2+ breast cancer patients. These findings demonstrate the importance of molecular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have important diagnostic and therapeutic consequences for the clinical management of HER2+ breast cancer. Gene expression analysis of Her2, Myc, and Her2 + Myc over expression on MCF10A cells, with MCF10A vector control comparison

2013-09-24 | E-GEOD-43730 | biostudies-arrayexpress

Pit-1 overexpression in the human breast adenocarcinoma MCF-7 cell line

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2014-12-12 | E-GEOD-64101 | biostudies-arrayexpress

Gene expression differences between matched male and female breast cancer

Project description:In this experiment, formalin-fixed paraffin-embedded male (n=15) and female (n=10) primary invasive ductal carcinoma (all ERÎ±-positive, HER2-negative, node-negative) samples were selected and hybridized using the Almac Diagnostics Breast Cancer DSA(TM) array ADXBRCv2a520413 in order to investigate the gene expression differences between male and female breast cancer.

2017-07-04 | E-MTAB-4040 | biostudies-arrayexpress

Modeling the ESR1 tyrosine 537 mutation with CRISPR-Cas9 for mechanistic studies and evaluation of therapeutic approaches for metastatic breast cancer [ChIP-Seq]

Project description:Estrogen receptor-Î± (ERÎ±) is an important driver of breast cancer and is the target for hormonal therapies, anti-estrogens and drugs that limit estrogen biosynthesis (aromatase inhibitors). Mutations in the ESR1 gene identified in metastatic breast cancer provide a potential mechanism for acquired resistance to hormone therapies. We have used CRISPR-Cas9 mediated genome editing in the MCF-7 breast cancer cell line, generating MCF-7-Y537S. MCF-7-Y537S cells encode a wild-type (tyrosine 537) and a mutant (serine 537) allele. Growth of the line is estrogen-independent and expression of ERÎ± target genes is elevated in the absence of estrogen. ER ChIP-seq was carried out to map global ERÎ± binding sites in the presence and absence of estrogen. RNA-seq following estrogen treatment was used for gene expression analysis. We show that expression of ER target genes and ER recruitment to ER binding regions is similar in MCF-7 and MCF-7-Y537S cells, except that ER recruitment to DNA and expression of ER target genes is frequently elevated in the absence of estrogen Hormone depleted MCF-7 LUC /Y537S mutant cells were treated with estrogen (10nM) or ETOH as vehicle control for 45 mins. ErÎ± Chip-seq was performed using Illumnia methodology

2016-10-25 | E-GEOD-78284 | biostudies-arrayexpress

A Myc transcriptional program that is independent of EMT drives a poor prognosis tumor-propagating phenotype in HER2+ breast cancer

2013-09-24 | GSE43730 | GEO

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