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Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer.

TitleTranscriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer.
Publication TypeJournal Article
Year of Publication2011
AuthorsSproul, D, Nestor, C, Culley, J, Dickson, JH, J Dixon, M, Harrison, DJ, Meehan, RR, Sims, AH, Ramsahoye, BH
JournalProc Natl Acad Sci U S A
Volume108
Issue11
Pagination4364-9
Date Published2011 Mar 15
ISSN1091-6490
KeywordsBreast, Breast Neoplasms, Cell Line, Tumor, Cell Lineage, CpG Islands, DNA Methylation, Embryonic Stem Cells, Epithelial Cells, Female, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Histones, Humans, Mesoderm, Organ Specificity, Repressor Proteins, Transcription, Genetic
Abstract

Aberrant promoter hypermethylation is frequently observed in cancer. The potential for this mechanism to contribute to tumor development depends on whether the genes affected are repressed because of their methylation. Many aberrantly methylated genes play important roles in development and are bivalently marked in ES cells, suggesting that their aberrant methylation may reflect developmental processes. We investigated this possibility by analyzing promoter methylation in 19 breast cancer cell lines and 47 primary breast tumors. In cell lines, we defined 120 genes that were significantly repressed in association with methylation (SRAM). These genes allowed the unsupervised segregation of cell lines into epithelial (EPCAM+ve) and mesenchymal (EPCAM-ve) lineages. However, the methylated genes were already repressed in normal cells of the same lineage, and >90% could not be derepressed by treatment with 5-aza-2'-deoxycytidine. The tumor suppressor genes APC and CDH1 were among those methylated in a lineage-specific fashion. As predicted by the epithelial nature of most breast tumors, SRAM genes that were methylated in epithelial cell lines were frequently aberrantly methylated in primary tumors, as were genes specifically repressed in normal epithelial cells. An SRAM gene expression signature also correctly identified the rare claudin-low and metaplastic tumors as having mesenchymal characteristics. Our findings implicate aberrant DNA methylation as a marker of cell lineage rather than tumor progression and suggest that, in most cases, it does not cause the repression with which it is associated.

DOI10.1073/pnas.1013224108
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID21368160
PubMed Central IDPMC3060255
Grant List / / Cancer Research UK / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom

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