Concordant epigenetic silencing of transforming growth factor-ß signaling pathway genes occurs early in breast carcinogenesis

No Thumbnail Available
File version
Author(s)
Hinshelwood, Rebecca A.
Huschtscha, Lily I.
Melki, John
Stirzaker, Clare
Abdipranoto, Andrea
Vissel, Bryce
Ravasi, Timothy
Wells, Christine
Hume, David A.
Reddel, Roger R.
Clark, Susan J.
Griffith University Author(s)
Primary Supervisor
Other Supervisors
Editor(s)
Date
2007
Size
File type(s)
Location
License
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 p16(INK4A) 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 beta (TGF-beta) 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-beta2, its receptors TGF-beta R1 and TGF-beta R2, and activator thrombospondin-1 are concordantly suppressed early in breast carcinogenesis by histone modifications and indicate that the TGF-beta signaling pathway is a novel target for gene activation by epigenetic therapy.

Journal Title

Cancer Research

Conference Title
Book Title
Edition
Volume

67

Issue

24

Thesis Type
Degree Program
School
Patent number
Funder(s)
Grant identifier(s)
Rights Statement
Rights Statement
Item Access Status
Note
Access the data
Related item(s)
Subject

Oncology and carcinogenesis

History, heritage and archaeology

Persistent link to this record
Citation
Collections