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| Status |
Public on Jun 05, 2008 |
| Title |
Epigenetic events in early breast cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Subpopulations of primary Human Mammary Epithelial Cells (HMEC) have the unique ability to escape a period of growth arrest and continue to proliferate. These cells, called post-selection or variant cells (vHMEC), share features with premalignant breast cancer lesions, including p16INK4A promoter hypermethylation. Epigenetic silencing of tumour suppressor genes through DNA methylation and histone modification is an early event in tumorigenesis. One of the main challenges is to find genes or gene pathways that are commonly silenced to provide early epigenetic diagnostic and therapeutic cancer targets. To identify very early epigenetic events that occur in breast cancer, we used microarrays to screen for gene pathways that were suppressed in post-selection HMECs, but reactivated after treatment with the demethylation agent 5-Aza-2’-deoxycytidine (5-Aza-dC). We found several members of the Transforming Growth Factor Beta (TGFb) signalling pathway (THBS1, TGFb2, TGFb R1 & TGFb R2) were consistently down-regulated in the post-selection HMEC population. Gene suppression was not associated with DNA methylation but was associated with chromatin remodelling, involving a decrease in histone H3 lysine 27 (H3K27) tri-methylation and an increase in histone H3 lysine 9 (H3K9) di-methylation and H3K9 de-acetylation. Similar epigenetic repression was also identified MDAMB453 breast cancer cells and in breast tumour samples. These results demonstrate for the first time that TGFb2, its receptors TGFb R1 & TGFb R2 and activator THBS1 are concordantly suppressed early in breast carcinogenesis by repressive histone modifications and indicate that the TGFb signalling pathway is a novel target for gene activation by epigenetic therapy.
Keywords: cell differentiation, breast cancer, gene silencing, epigenetics
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| Overall design |
Two-colour reference design was used. Two biological replicates were included in the study - Bre60 and Bre-80. Each cell line was sampled at pre-selection stage, post-selection stage and post AZA treatment. The post-selection stage was chosen as the reference sample, and a control post-post hybridisation included to assess variability across the assay.
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| Contributor(s) |
Hinshelwood RA, Huschtscha LI, Melki J, Stirzaker C, Ravasi T, Wells C, Hume DA, Reddel RR, Clark SJ |
| Citation(s) |
18089780 |
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| Submission date |
Jun 04, 2007 |
| Last update date |
Jul 31, 2013 |
| Contact name |
Milena Gongora |
| E-mail(s) |
milenagongora@gmail.com
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| Organization name |
Institute for Molecular Biosciences
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| Street address |
bld 80, services rd
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| City |
St. Lucia |
| State/province |
QLD |
| ZIP/Postal code |
4072 |
| Country |
Australia |
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| Platforms (1) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA100797 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE8007_RAW.tar |
2.3 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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