Show simple item record

dc.contributor.authorHinshelwood, Rebecca A.
dc.contributor.authorHuschtscha, Lily I.
dc.contributor.authorMelki, John
dc.contributor.authorStirzaker, Clare
dc.contributor.authorAbdipranoto, Andrea
dc.contributor.authorVissel, Bryce
dc.contributor.authorRavasi, Timothy
dc.contributor.authorWells, Christine
dc.contributor.authorHume, David A.
dc.contributor.authorReddel, Roger R.
dc.contributor.authorClark, Susan J.
dc.date.accessioned2017-05-03T15:01:02Z
dc.date.available2017-05-03T15:01:02Z
dc.date.issued2007
dc.date.modified2008-12-18T06:56:27Z
dc.identifier.issn15387445
dc.identifier.doi10.1158/0008-5472.CAN-07-1284
dc.identifier.urihttp://hdl.handle.net/10072/18507
dc.description.abstractHuman 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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research
dc.publisher.placeUSA
dc.publisher.urihttp://cancerres.aacrjournals.org/
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom11517
dc.relation.ispartofpageto11527
dc.relation.ispartofissue24
dc.relation.ispartofjournalCancer Research
dc.relation.ispartofvolume67
dc.rights.retentionY
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchHistory, heritage and archaeology
dc.subject.fieldofresearchcode3211
dc.subject.fieldofresearchcode43
dc.titleConcordant epigenetic silencing of transforming growth factor-ß signaling pathway genes occurs early in breast carcinogenesis
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.date.issued2007
gro.hasfulltextNo Full Text
gro.griffith.authorWells, Christine


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record