Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

ABSTRACT: The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.

ORGANISM(S): Homo sapiens

SUBMITTER: xiaoyang zhang

PROVIDER: E-GEOD-37323 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer.

Magnani Luca L Stoeck Alexander A Zhang Xiaoyang X Lánczky András A Mirabella Anne C AC Wang Tian-Li TL Gyorffy Balázs B Lupien Mathieu M

Proceedings of the National Academy of Sciences of the United States of America 20130401 16

The estrogen receptor (ER)α drives growth in two-thirds of all breast cancers. Several targeted therapies, collectively termed endocrine therapy, impinge on estrogen-induced ERα activation to block tumor growth. However, half of ERα-positive breast cancers are tolerant or acquire resistance to endocrine therapy. We demonstrate that genome-wide reprogramming of the chromatin landscape, defined by epigenomic maps for regulatory elements or transcriptional activation and chromatin openness, underli ...[more]

PMID: 23576735

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Project description:We report the genome-wide mapping of time-series ChIP-seq data sets of human ERα cell lines (MCF-7). The 4 time points cover 0, 1, 4 and 24 hours, respectively. MCF7 cells were maintained in a hormone-free medium (phenol red–free MEM with 2 mmol/L L-glutamine, 0.1 mmol/L nonessential amino acids, 50 units/mL penicillin, 50 Ag/mL streptomycin, 6 ng/mL insulin, and 10% charcoal-stripped FBS) for three days. MCF7 cells were treated with DMSO (as 0 hour time point) or E2 (108 mol/L) for 1, 4 and 24 hours. 5 x 107 cells were cross-linked with 1% formaldehyde for 10 min, at which point 0.125 M glycine was used to stop the crosslinking. In brief, after crosslinking, cells were treated by lysis buffers and sonicated to fragment the chromatin to a size range of 500bp-1kb. Chromatin fragments were then immunoprecipitated with 10ug of antibody/magnetic beads. The antibodies against ERα were purchased from Santa Cruz Biotechnology (Santa Cruz, sc-8005 X). After immunoprecipitation, washing, and elution, ChIP DNA was purified by phenol:chloroform:isoamyl alcohol and solubilized in 70 μl of water. The ChIP DNA sample was run in 12% PAGE and the 100-300bp DNA fraction was excised and eluted from the gel slice overnight at 4 °C in 300 μl of elution buffer (5:1, LoTE buffer (3 mM Tris-HCl, pH 7.5, 0.2 mM EDTA)-7.5 M ammonium acetate) and was purified using a QIAquick purification kit (Qiagen, Cat#28104). The library was constructed using Illumina genomic DNA prep kit by following its protocol (Illumina, cat# FC-102-1002), clusters were generated on the Illumina cluster station (Illumina, cat# FC-103-1002), DNA samples (20 nM per sample) quantified by an Agilent Bioanalyzer, were loaded onto Illumina Genome Analyzer IIx (GAIIx) for sequencing according to the manufacturer’s protocol. Reads generated from the Illumina GAIIx pipeline were aligned to the Human Genome Assembly (NCBI build 36.1/hg18) using ELAND algorithm. Experiments on human ERα breat cancer cell lines (MCF-7) in 4 time points.

Dataset Information

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

Publications

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer.

Similar Datasets

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