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: We report that 1) in pilot experiments, the in vitro treatment of estrogen receptor (ER)- positive and BRCA-1 wild-type breast epithelial cells with TCDD attenuates 17beta-estradiol (E2)-dependent stimulation of BRCA-1 protein and induces hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a; 2) TCDD enhances the association of the AhR, DNA methyl transferases (DNMT)1, DNMT3a, and DNMT3b; methyl binding protein (MBD)2; and tri-methylated H3K9 (3meH3K9) with the BRCA-1 promoter; 3) The phytoalexin resveratrol, selected as a prototype dietary AhR antagonist, antagonizes at physiologically relevant doses (1 micronmol/L) the TCDD-induced repression of BRCA-1 protein, BRCA-1 promoter methylation, and the recruitment of the AhR, MBD2, 3meH3K9, and DNMTs (1, 3a, and 3b); 4) In-utero treatment with TCDD increases the percentage of terminal end-buds in female offspring; 5) We have optimized measurements of BRCA-1 expression in mammary tissue. Measurements are in progress to examine the effects in utero of TCDD exposure on BRCA-1 expression and promoter hypermethylation in mammary tissue of female offspring. Significance: Taken together, these observations provide preliminary evidence AhR activation is a risk factor in the etiology of sporadic breast cancer through BRCA-1 silencing and provide the molecular basis for prevention programs based on dietary AhR antagonists.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2011
- Accession Number
- ADA545581
Entities
People
- Donato Romagnolo
Organizations
- University of Arizona