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Series GSE95302 Query DataSets for GSE95302
Status Public on Jun 01, 2020
Title DNA structure-specific endonuclease FEN1 as a novel drug target in tamoxifen resistant breast cancer.
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional-activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα-function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex-vivo cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof-of-principle for FEN1 blockade in tamoxifen-resistant breast cancer.
 
Overall design RNA-seq and Chip-seq of ERα, FOXA1, XRCC1, PCNA, POLII, PARP1, XRCC1, BRG1 and FAIRE-seq in MCF-7 cells treated with siRNAs or FEN1 inhibitor
RRBS of MCF-7 cells treated -+ 45 min E2 -+ FEN1 inhibitor
 
Contributor(s) Flach KD, Zwart W
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Submission date Feb 23, 2017
Last update date Jun 03, 2020
Contact name Koen Flach
E-mail(s) koenflach@hotmail.com
Organization name NKI
Street address Plesmanlaan 121
City Amsterdam
ZIP/Postal code 1066CX
Country Netherlands
 
Platforms (2)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (33)
GSM2501550 Chip-seq of ERα in MCF-7 cells transfected with non-targeting siRNA
GSM2501551 Chip-seq of ERα in MCF-7 cells transfected with siRNA targeting FEN1
GSM2501554 Chip-seq of FOXA1 in MCF-7 cells transfected with non-targeting siRNA
Relations
BioProject PRJNA376593
SRA SRP100642

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE95302_DESeq_normalized_counts.csv.gz 3.4 Mb (ftp)(http) CSV
GSE95302_RAW.tar 1.2 Mb (http)(custom) TAR (of BED)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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