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

A. F. Trombino, R. I. Near, R. A. Matulka, S. Yang, L. J. Hafer, P. A. Toselli, D. W. Kim, A. E. Rogers, G. E. Sonenshein, D. H. Sherr

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Abstract

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)/transcription factor. Historically, investigations into AhR-regulated carcinogenesis have focused on AhR-dependent transcriptional regulation of cytochrome P450 (CYP) enzymes which oxidize PAH to mutagenic intermediates. However, recent studies suggest that the AhR directly regulates cell growth. Given the postulated role of the AhR in carcinogenesis, we predicted that: (1) tissue predisposed to PAH tumorigenesis would express the AhR and (2) aberrant AhR and/or AhR-regulated gene expression would accompany malignant transformation. To test these hypotheses, AhR and CYP1 protein and/or mRNA levels were evaluated in rat mammary tumors induced with 7, 12-dimethylbenz[a]anthracene (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 6h of DMBA gavage, only CYP1B1 mRNA remained elevated in tumors. These results: (1) help explain targeting of breast tissue by carcinogenic PAH, (2) imply that AhR and CYP1B1 hyper-expression represent molecular biomarkers for, at least, PAH-induced mammary cell transformation, and (3) suggest mechanisms through which the AhR may contribute to carcinogenesis well after exogenous AhR ligands have been eliminated.

Original languageEnglish (US)
Pages (from-to)117-131
Number of pages15
JournalBreast Cancer Research and Treatment
Volume63
Issue number2
DOIs
StatePublished - 2000

Fingerprint

Aryl Hydrocarbon Receptors
Carcinogenesis
Breast
Transcription Factors
Genes
Polycyclic Aromatic Hydrocarbons
9,10-Dimethyl-1,2-benzanthracene
Messenger RNA
Cytochrome P-450 Enzyme System
Neoplasms
Epithelial Cells
Breast Neoplasms
Ligands

Keywords

  • Aryl hydrocarbon receptor
  • Breast tumors
  • CYP1
  • Tumorigenesis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis. / Trombino, A. F.; Near, R. I.; Matulka, R. A.; Yang, S.; Hafer, L. J.; Toselli, P. A.; Kim, D. W.; Rogers, A. E.; Sonenshein, G. E.; Sherr, D. H.

In: Breast Cancer Research and Treatment, Vol. 63, No. 2, 2000, p. 117-131.

Research output: Contribution to journalArticle

Trombino, AF, Near, RI, Matulka, RA, Yang, S, Hafer, LJ, Toselli, PA, Kim, DW, Rogers, AE, Sonenshein, GE & Sherr, DH 2000, 'Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis', Breast Cancer Research and Treatment, vol. 63, no. 2, pp. 117-131. https://doi.org/10.1023/A:1006443104670
Trombino, A. F. ; Near, R. I. ; Matulka, R. A. ; Yang, S. ; Hafer, L. J. ; Toselli, P. A. ; Kim, D. W. ; Rogers, A. E. ; Sonenshein, G. E. ; Sherr, D. H. / Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis. In: Breast Cancer Research and Treatment. 2000 ; Vol. 63, No. 2. pp. 117-131.
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AU - Near, R. I.

AU - Matulka, R. A.

AU - Yang, S.

AU - Hafer, L. J.

AU - Toselli, P. A.

AU - Kim, D. W.

AU - Rogers, A. E.

AU - Sonenshein, G. E.

AU - Sherr, D. H.

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