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 have developed colonies through breeding of AhR and BRCA-1 conditional mammary tissue knockouts. Pregnant mice from each group have been treated with the AhR agonist TCDD. Mammary tissues from offspring are being collected for analysis of BRCA-1 expression and methylation, and markers of cell proliferation and morphology.
