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Gene expression analysis & Comparative genomic hybridization from Lung cancer Cell lines

ABSTRACT: Gene expression and Comparative genomic hybridization (CGH) microarrays performed in a set of 8 Lung cancer Cell lines. The search for oncogenes is becoming increasingly important in cancer genetics because they constitute suitable targets for therapeutic intervention. To identify novel oncogenes, activated by gene amplification, we performed high-resolution CGH (Comparative Genome Hybridization) analysis on cDNA microarrays and compared DNA copy number and mRNA expression levels in lung cancer cell lines. We have performed both microarrays (expression and CGH) in a set of 8 human lung cancer cell lines: Calu3, H23, H441, A427, H522, A549, H1299, H2126.

ORGANISM(S): Homo sapiens

SUBMITTER: Medina PP

PROVIDER: S-ECPF-GEOD-14079 | biostudies-other | 2009 Apr

REPOSITORIES: biostudies-other

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Project description: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. RNA-Seq in breast cancer cell-lines transfected with JARID1B/CTCF/control siRNA. 50 cycles of sequencing on Illumina platform.

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Gene expression analysis & Comparative genomic hybridization from Lung cancer Cell lines

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