Gestational Exposure as Epigenetic Modifier of Breast Cancer Risk
Abstract
Information from animal models and population studies suggest that mammary tumor promotion in adult life is influenced by prior exposure to carcinogens in early life. The main purpose of this project is to investigate whether or not activation of the aromatic hydrocarbon receptor (AhR) induces CpG methylation at the BRCA-1 gene, and if this epigenetic event predisposes to development of triple-negative breast cancers (TNBC). Major findings: Preliminary data acquired through the support of this grant indicate that: 1) targeting of the AhR with an AhR antagonist in cell culture experiments with human breast cancer cells harboring hypermethylated BRCA-1 reactivates BRCA-1 and estrogen receptor-expression; 2) Comparative analyses of human breast tumors indicate the existence of a correlation between higher BRCA-1 promoter methylation and overexpression of AhR in TNBC, but not in luminal type A and B, or Her2-positive breast cancers; and 3) We are developing colonies through breeding of AhR and BRCA-1 conditional mammary tissue knockouts that will allow us to test the interaction between BRCA-1 and AhR genotype on developmental effects of AhR activation on BRCA-1 expression and promoter methylation. Significance: these data provide preliminary evidence that overexpression/activation of the AhR contributes to a TBNC phenotype characterized by increased BRCA-1 promoter methylation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1004108
Entities
People
- Donato F. Romagnolo
- Ornella I. Selmin
Organizations
- University of Arizona