Concordant Epigenetic silencing of transforming growth factor -beta signalling pathway genes occurs early in breast carcinogenesis

Hinshelwood, Rebecca A., Huschtscha, Lily I., Melki, John, Stirzaker, Clare, Abdipranoto, Andrea, Vissel, Bryce, Ravasi, Timothy, Wells, Christine A., Hume, David A., Reddel, Roger R. and Clark, Susan J. (2007) Concordant Epigenetic silencing of transforming growth factor -beta signalling pathway genes occurs early in breast carcinogenesis. Cancer Research, 67 24: 11517-11527. doi:10.1158/0008-5472.CAN-07-1284

Author Hinshelwood, Rebecca A.
Huschtscha, Lily I.
Melki, John
Stirzaker, Clare
Abdipranoto, Andrea
Vissel, Bryce
Ravasi, Timothy
Wells, Christine A.
Hume, David A.
Reddel, Roger R.
Clark, Susan J.
Title Concordant Epigenetic silencing of transforming growth factor -beta signalling pathway genes occurs early in breast carcinogenesis
Formatted title
Concordant Epigenetic silencing of transforming growth factor -ßsignalling pathway genes occurs early in breast carcinogenesis
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2007
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-07-1284
Volume 67
Issue 24
Start page 11517
End page 11527
Total pages 11
Place of publication Philadelphia
Publisher Amer Assoc cancer research
Collection year 2008
Language eng
Subject 321015 Oncology and Carcinogenesis
730108 Cancer and related disorders
Abstract Human mammary epithelial cells (HMEC) grown under standard cell culture conditions enter a growth phase referred to as selection, but a subpopulation is able to escape from arrest and continue to proliferate. These cells, called post-selection or variant HMECs, may be derived from progenitor cells found in normal mammary epithelium that subsequently acquire premalignant lesions, including p16INK4A promoter hypermethylation. Epigenetic silencing of tumor suppressor genes through DNA methylation and histone modification is an early event in tumorigenesis. A major challenge 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. We found that several members of the transforming growth factor β (TGF-β) signaling pathway were consistently down-regulated in the post-selection HMEC populations, and this was associated with a marked decrease in Smad4 nuclear staining. Gene suppression was not associated with DNA methylation but with chromatin remodeling, involving a decrease in histone H3 lysine 27 trimethylation and an increase in histone H3 lysine 9 dimethylation and deacetylation. These results show for the first time that TGF-β2, its receptors TGF-βR1 and TGF-βR2, and activator thrombospondin-1 are concordantly suppressed early in breast carcinogenesis by histone modifications and indicate that the TGF-β signaling pathway is a novel target for gene activation by epigenetic therapy.
Keyword growth
Epigenetic silencing
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2008 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 58 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 29 Apr 2008, 15:19:51 EST by Cody Mudgway on behalf of Institute for Molecular Bioscience