Epigenetic Regulation of Breast Cancer Type-1 Gene by the Activated Aromatic Hydrocarbon Receptor and the Preventative Effects of Resveratrol

Persistent Link:
http://hdl.handle.net/10150/228436
Title:
Epigenetic Regulation of Breast Cancer Type-1 Gene by the Activated Aromatic Hydrocarbon Receptor and the Preventative Effects of Resveratrol
Author:
Papoutsis, Andreas
Issue Date:
2012
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Epigenetic mechanisms may contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast cancers. Through environmental exposure and diet, humans are exposed to xenobiotics and food compounds that bind the aromatic hydrocarbon receptor (AhR). AhR-ligands include the dioxin-like and tumor promoter 2,3,7,8 tetrachlorobenzo-p-dioxin (TCDD). The activated AhR regulates transcription through binding to xenobiotic response elements (XRE=GCGTG) and interactions with transcription cofactors. Previously, we reported on the presence of several XRE in the proximal BRCA-1 promoter, and that the expression of endogenous AhR was required for silencing of BRCA-1 expression by TCDD. Here, we document that in estrogen receptor-alpha-positive and BRCA-1 wild-type MCF-7 breast cancer cells, the treatment with TCDD attenuated 17-beta estradiol (E2)-dependent stimulation of BRCA-1 protein and induced hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a. Additionally, we found that TCDD enhanced the association of the AhR, DNA methyl transferases (DNMT)1, DNMT3a, and DNMT3b; methyl binding protein (MBD)2; and tri-methylated H3K9 (H3K9me3) with the BRCA-1 promoter. Conversely, the phytoalexin resveratrol, selected as a prototype dietary AhR antagonist, antagonized at physiologically relevant doses the TCDD-induced repression of BRCA-1 protein, BRCA-1 promoter methylation, and the recruitment of the AhR, MBD2, H3K9me3, and DNMTs (1, 3a, and 3b). Taken together, these observations provide evidence for a mechanistic role for AhR-agonists in establishment of BRCA-1 promoter hypermethylation and the basis for the development of prevention strategies based on AhR antagonists.
Type:
text; Electronic Dissertation
Keywords:
epigenetics; resveratrol; Nutritional Sciences; Aromatic hydrocarbon receptor; BRCA-1
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Nutritional Sciences
Degree Grantor:
University of Arizona
Advisor:
Romagnolo, Donato

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleEpigenetic Regulation of Breast Cancer Type-1 Gene by the Activated Aromatic Hydrocarbon Receptor and the Preventative Effects of Resveratrolen_US
dc.creatorPapoutsis, Andreasen_US
dc.contributor.authorPapoutsis, Andreasen_US
dc.date.issued2012-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractEpigenetic mechanisms may contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast cancers. Through environmental exposure and diet, humans are exposed to xenobiotics and food compounds that bind the aromatic hydrocarbon receptor (AhR). AhR-ligands include the dioxin-like and tumor promoter 2,3,7,8 tetrachlorobenzo-p-dioxin (TCDD). The activated AhR regulates transcription through binding to xenobiotic response elements (XRE=GCGTG) and interactions with transcription cofactors. Previously, we reported on the presence of several XRE in the proximal BRCA-1 promoter, and that the expression of endogenous AhR was required for silencing of BRCA-1 expression by TCDD. Here, we document that in estrogen receptor-alpha-positive and BRCA-1 wild-type MCF-7 breast cancer cells, the treatment with TCDD attenuated 17-beta estradiol (E2)-dependent stimulation of BRCA-1 protein and induced hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a. Additionally, we found that TCDD enhanced the association of the AhR, DNA methyl transferases (DNMT)1, DNMT3a, and DNMT3b; methyl binding protein (MBD)2; and tri-methylated H3K9 (H3K9me3) with the BRCA-1 promoter. Conversely, the phytoalexin resveratrol, selected as a prototype dietary AhR antagonist, antagonized at physiologically relevant doses the TCDD-induced repression of BRCA-1 protein, BRCA-1 promoter methylation, and the recruitment of the AhR, MBD2, H3K9me3, and DNMTs (1, 3a, and 3b). Taken together, these observations provide evidence for a mechanistic role for AhR-agonists in establishment of BRCA-1 promoter hypermethylation and the basis for the development of prevention strategies based on AhR antagonists.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectepigeneticsen_US
dc.subjectresveratrolen_US
dc.subjectNutritional Sciencesen_US
dc.subjectAromatic hydrocarbon receptoren_US
dc.subjectBRCA-1en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineNutritional Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorRomagnolo, Donatoen_US
dc.contributor.committeememberWondrak, Georgen_US
dc.contributor.committeememberBowden, G. Timothyen_US
dc.contributor.committeememberHowell, Wandaen_US
dc.contributor.committeememberSelmin, Ornellaen_US
dc.contributor.committeememberRomagnolo, Donatoen_US
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