Expression of the aryl hydrocarbon receptor/transcription factor (AhR) andAhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis

Exposure to ubiquitous environmental chemicals, such as polycyclic aromatic hydrocarbons (PAH), may contribute to human breast cancer. In animals, PAH induce tumors in part by activating the aryl hydrocarbon receptor (AhR)/tr anscription factor. Historically, investigations into AhR-regulated carcino genesis have focused on AhR-dependent transcriptional regulation of cytochr ome P450 (CYP) enzymes which oxidize PAH to mutagenic intermediates. Howeve r, recent studies suggest that the AhR directly regulates cell growth. Give n the postulated role of the AhR in carcinogenesis, we predicted that: (1) tissue predisposed to PAH tumorigenesis would express the AhR and (2) aberr ant AhR and/or AhR-regulated gene expression would accompany malignant tran sformation. To test these hypotheses, AhR and CYP1 protein and/or mRNA leve ls were evaluated in rat mammary tumors induced with 7, 12-dimethylbenz[a]a nthracene (DMBA), a prototypic PAH and AhR ligand. Results indicate modest AhR expression in normal mammary myoepithelial and ductal epithelial cells. In contrast, high AhR levels were detected in DMBA-induced tumors. Nuclear AhR localization in tumors suggested constitutive AhR activation. In situ hybridization and quantitative RT-PCR assays indicated high AhR mRNA levels in neoplastic epithelial cells. While both AhR-regulated CYP1A1 and CYP1B1 mRNAs were induced in breast tissue within 6 h of DMBA gavage, only CYP1B1 mRNA remained elevated in tumors. These results: (1) help explain targetin g of breast tissue by carcinogenic PAH, (2) imply that AhR and CYP1B1 hyper -expression represent molecular biomarkers for, at least, PAH-induced mamma ry cell transformation, and (3) suggest mechanisms through which the AhR ma y contribute to carcinogenesis well after exogenous AhR ligands have been e liminated.