Epigenetic Programming of Breast Cancer and Nutrition Prevention
Abstract
The purpose of this project is to investigate whether epigenetic mechanisms may contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast cancers. The scope is to test the role of 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. Major findings: Gestational exposure to TCDD increased levels of methylation of a CpG region comprising an XRE harbored in the BRCA-1 promoter. This enrichment was paralleled by increased recruitment of DNMT1, decreased BRCA-1 mRNA and protein expression, reduced mammary gland structures associated with differentiation, and mRNA increases of cell cycle regulatory protein cyclin D1 and cdk4. Conversely, cotreatment with the dietary compound resveratrol (Res) had protective effects on TCDD-induced BRCA-1 methylation, BRCA- 1 expression, and changes in mammary gland development. Significance. These data provide new insight into the impact of gestational exposure on epigenetic events induced by the AhR on the BRCA-1 gene.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2012
- Accession Number
- ADA563411
Entities
People
- Donato F. Romagnolo
- Ornella Selmin
Organizations
- University of Arizona