ToxSci Advance Access published online on May 21, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm125
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A Proposed Mechanism for the Protective Effect of Dioxin Against Breast Cancer
MECHANISM FOR CANCER PROTECTION BY DIOXIN
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,*,¶
* Molecular Toxicology Interdepartmental Doctoral Program, School of Public Health
Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, USA
Current address: 6 Paddock Lane, Great Neck, NY 11020
Current address: UT M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 0432, Houston, TX 77030
¶ To whom correspondence should be addressed: Department of Pathology and Laboratory Medicine, Box 951732 Center for Health Sciences, University of California Los Angeles, Los Angeles, CA 90095-1732; E-mail: ohank{at}mednet.ucla.edu; Phone: (310) 825-2936; Fax: (310) 794-9272
Received March 21, 2007; revision received May 11, 2007; accepted May 14, 2007
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Abstract |
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Although it is causative for many types of cancers, experimental and epidemiological evidence suggest that 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) may in fact protect against breast cancer. The mechanism(s) for this protection remain unclear. In an attempt to further elucidate this mechanism, we performed a microarray experiment to identify genes that were modulated upon dioxin treatment. We found that dioxin down-regulated the mRNAs for the G-protein coupled receptor, CXCR4, as well as its unique chemokine ligand, CXCL12, in MCF-7 breast cancer cells. We demonstrated that the corresponding proteins are also down-regulated by dioxin. The interaction between CXCR4 and CXCL12 plays a central role in the metastasis of breast cancer, as disruption of the CXCL12/CXCR4 axis has been shown to limit the metastasis of breast cancer cells to the lung in mice. Utilizing an in vitro chemotaxis assay, we demonstrate that dioxin specifically inhibits the migration of MCF-7 cells towards CXCL12. We also show that dioxin reduces CXCR4 under hypoxia and CXCL12 under estradiol-induced conditions in MCF-7 cells. Finally, as the CXCR4/CXCL12 axis is implicated in the progression of numerous types of cancer, we identified several other cancer cell lines in which dioxin modulates CXCR4 and CXCL12 levels. We therefore propose that one mechanism whereby dioxin may protect against breast cancer is via down-regulation of CXCR4 and CXCL12, thereby inhibiting progression of the disease. Further, other non-toxic ligands for the AHR (Selective Aryl Hydrocarbon Receptor Modulators) may exert their protective effects by a similar mechanism.
Key Words: dioxin; CXCR4; CXCL12; breast cancer; AHR; chemokine receptor.