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Series GSE99626 Query DataSets for GSE99626
Status Public on Dec 31, 2017
Title Combinatorial Reprogramming of Estrogen Signaling by the Nuclear Receptor Family 3C
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Estrogen receptor (ER) positive breast cancers exist in a complex environment of steroid hormones and their cognate receptors. Receptors for estrogens, progestogens (PR), androgens (AR), glucocorticoids (GR) and mineralocorticoids (MR) are variably expressed in these hormone- sensitive breast cancers. Clinical translation of crosstalk among these receptors has been limited by an incomplete understanding of ER reprogramming by PR, GR, AR and MR (NR3C receptors). This study reports that each of the NR3C receptors reprograms ER chromatin binding to sites enriched for NR3C binding motifs and that hormonal co-treatment increases the likelihood of ER binding to estrogen response elements. A major overlap is observed among ER conserved sites, but not among ER sites that are lost or gained due to reprogramming by each of the NR3C receptors. This stability of ER genomic binding is reflected in the resulting transcriptomes, as there is significant overlap among genes whose expression is unaltered in response to joint hormonal interventions but not among genes whose expression is enhanced or opposed by an individual NR3C receptor. The addition of NR3C ligands can enhance or oppose estrogen-mediated induction and repression of gene transcription, resulting in net agonism or antagonism of ER-mediated actions at gene loci and of cellular pathways of interest. In addition to differential modulation of chromatin binding, differences in cofactor associations for ER, PR and GR likely contribute to the divergent functions of these receptors in breast cancer. Among the NR3C receptors, MR activation differentially reprograms ER chromatin binding and, in contrast to ligands for PR, GR or AR, the MR ligand aldosterone does not inhibit estrogen-induced cell proliferation or potentiate the anti-proliferative effect of tamoxifen in ER+ MCF7 cells. PR, GR, AR and MR may be functionally relevant in ER+ breast cancer because higher expression of these NR3C receptors; or genes whose estrogen-regulated expression is altered by each of these receptors is significantly associated with better overall and relapse-free survival. In summary, this study highlights the diverse yet overlapping activities of NR3C receptors in reprogramming ER signaling.
 
Overall design Model systems were deprived of steroids by culturing them in phenol red free RPMI 1640 media that is supplemented with 10% charcoal-stripped fetal bovine serum and 1% penicillin/streptomycin. Subsequently, these steroid-deprived models were treated with either vehicle, 10 nM estradiol, 10 nM of NR3C ligand (Progesterone, Dexamethasone, DHT or Aldosterone) or 10 nM of both estradiol and NR3C ligand for the time duration mentioned in the paper. Subsequently anti-ER ChIP-seq and polyA-selected mRNA-seq was performed on the treated cells.
 
Contributor(s) Greene G, Singhal H
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Submission date Jun 02, 2017
Last update date May 15, 2019
Contact name Hari Singhal
E-mail(s) hari_singhal@dfci.harvard.edu
Organization name University of Chicago
Department Ben May Department for Cancer Research
Lab Geoffrey L Greene
Street address 929 E 57th St
City Chicago
State/province IL
ZIP/Postal code 60637
Country USA
 
Platforms (3)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (62)
GSM2125141 MCF7_Vehicle_45 mins_ERChIP (H2)
GSM2125143 MCF7_E2_45 mins_ERChIP (H4)
GSM2125145 MCF7_DHT_45 mins_ERChIP
Relations
BioProject PRJNA389107
SRA SRP108515

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE99626_AI012_T47D_ReadCounts.csv.gz 1.2 Mb (ftp)(http) CSV
GSE99626_RAW.tar 24.2 Mb (http)(custom) TAR (of BED, CSV, NARROWPEAK)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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