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Series GSE49794 Query DataSets for GSE49794
Status Public on Jun 17, 2014
Title DNA methylation analysis of breast cancer cell-lines
Organism Homo sapiens
Experiment type Methylation profiling by genome tiling array
Summary Recurrent mutations in histone modifying enzymes in multiple cancer types imply key roles in tumorigenesis. However, the functional relevance of these mutations remains unknown. Here we show that the JARID1B histone H3 lysine 4 demethylase is frequently amplified and overexpressed in luminal breast tumors and a somatic point mutation of JARID1B leads to the gain of luminal-specific gene expression programs. Downregulation of JARID1B in luminal breast cancer cells induces the expression of basal cell-specific genes and growth arrest, which is partially rescued by the inhibition of TGFBR thereby indicating a key role for TGFb signaling. Integrated genome-wide analysis of JARID1B chromatin binding, histone H3 lysine trimethyl (H3K4me3) and dimethyl (H3K4me2) patterns, and gene expression profiles in luminal and basal-like breast cancer cells suggest a key role for JARID1B in luminal cell-specific gene expression programs. A significant fraction of JARID1B binding-sites overlaps with CTCF in both luminal and basal-like breast cancer cells. CTCF also co-immunoprecipitates with JARID1B and it may influence its histone demethylase (HDM) activity as the H3K4me3/me2 ratio is lower at the CTCF-overlapping compared to JARID1B-unique sites. Additionally, a heterozygous JARID1B missense mutation (K1435R) in the HCC2157 basal-like breast cancer cell line is associated with unique JARID1B chromatin-binding and gene expression patterns implying gain of luminal features. In line with this, exogenous expression of this mutant in basal-like breast cancer cells leads to a gain of JARID1B binding at many luminal-specific genes. A PARADIGM score reflecting JARID1B activity in luminal breast cancer cells is associated with poor clinical outcome in patients with luminal breast tumors. Together, our data imply that JARID1B is a luminal lineage-driving oncogene and that its therapeutic targeting may represent a novel therapeutic strategy in treatment-resistant luminal breast tumors.
Overall design Bisulphite converted DNA from 5 breast cancer cell lines were hybridised to the Illumina Infinium HumanMethylation450 BeadChip.
Contributor(s) Yamamoto S
Citation(s) 24937458
Submission date Aug 12, 2013
Last update date Mar 22, 2019
Contact name Kornelia Polyak
Phone 617-632-2106
Organization name Dana-Farber Cancer Institute
Department Medical Oncology
Lab Polyak
Street address 450 Brookline Ave
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
Platforms (1)
GPL13534 Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482)
Samples (5)
GSM1207161 SUM159
GSM1207162 T47D
GSM1207163 MCF7
This SubSeries is part of SuperSeries:
GSE46073 Gene expression and genome-wide location analysis of breast cancer cell-lines
BioProject PRJNA214937

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
GSE49794_RAW.tar 183.1 Mb (http)(custom) TAR
GSE49794_methylated_unmethylated_intensities.txt.gz 13.4 Mb (ftp)(http) TXT
Processed data included within Sample table

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