Cyclooxygenase-2 Promoter Activation by the Aromatic Hydrocarbon Receptor in Breast Cancer MCF-7 Cells: Repressive Effects of Conjugated Linoleic Acid

Abstract

The role of the aromatic hydrocarbon receptor (AhR) in transcriptional regulation of the human cyclooxygenase-2 (COX-2) gene remains elusive. We report that the AhR-ligands benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced transcription activity of COX-2 in breast cancer MCF-7 cells. The TCDD-dependent activation of the COX-2 promoter was abrogated by mutation of 2 xenobiotic response elements (XREs) = CGTG). We found that TCDD stimulated the binding of the AhR to COX-2 and cytochrome P4501A1 (CYP1A1) oligonucleotides containing consensus XREs. Conversely, the cotreatment with TCDD plus a mixture of conjugated linoleic acid (CLA) or selected CLA isomers prevented (CLAmix = t10,c12-CLA > c9,t11-CLA) the induction of transcription from the COX-2 promoter. The TCDD-induced binding of the AhR to COX-2 and CYP1A1 oligonucleotides was repressed by cotreatment with CLA (t10,c12-CLA > c9,t11-CLA), and the AhR antagonists, 3-methoxy-4-naphthoflavone, and resveratrol. We conclude that the AhR may be a suitable target for prophylactic strategies that target COX-2 expression.

Acknowledgments and Notes

We thank Dr. McIntyre, University of Utah, Salt Lake City, and Dr. David S. Pasco, University of Mississippi, Oxford for providing, respectively, the expression vector p3.9COX-2 and pCYP1A1–4XRE. We gratefully acknowledge E. A. Mash (Southwest Environmental Health Sciences Core Facility, University of Arizona, Tucson, AZ) for synthesis of 3M4NF. TCDD has been supplied by the National Cancer Institute (NCI), Division of Cancer Biology, Chemical and Physical Carcinogenesis Branch and distributed by Midwest Research Institute under a contract to NCI (64 CFR 72090, 64 CFR 28205). This work was supported in part by fellowships from Graduate Training Program T32 ES-07091-24 (J. K. Hockings and S. C. Degner) and a grant (100116) from the Arizona Biomedical Research Commission (D. F. Romagnolo). S. C. Degner and M. Q. Kemp contributed equally to the manuscript.