Hsu Erin L, Yoon Diana, Choi Hyun Ho, Wang Feng, Taylor Robert T, Chen Natalie, Zhang Ruixue, Hankinson Oliver
Molecular Toxicology Interdepartmental Doctoral Program, School of Public Health, University of California Los Angeles, Los Angeles, CA 90095-1732, USA.
Toxicol Sci. 2007 Aug;98(2):436-44. doi: 10.1093/toxsci/kfm125. Epub 2007 May 21.
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 downregulated the messenger RNAs 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 downregulated 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 toward 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 downregulation of CXCR4 and CXCL12, thereby inhibiting progression of the disease. Further, other nontoxic ligands for the aryl hydrocarbon receptor (selective AHR modulators) may exert their protective effects by a similar mechanism.
尽管2,3,7,8-四氯二苯并对二恶英（二恶英）是多种癌症的致病因素，但实验和流行病学证据表明，它实际上可能预防乳腺癌。这种保护作用的机制尚不清楚。为了进一步阐明这一机制，我们进行了一项微阵列实验，以鉴定二恶英处理后被调节的基因。我们发现，二恶英下调了MCF-7乳腺癌细胞中G蛋白偶联受体CXCR4及其独特的趋化因子配体CXCL12的信使核糖核酸。我们证明相应的蛋白质也被二恶英下调。CXCR4和CXCL12之间的相互作用在乳腺癌转移中起核心作用，因为CXCL12/CXCR4轴的破坏已被证明可限制乳腺癌细胞在小鼠体内向肺部的转移。利用体外趋化性测定，我们证明二恶英特异性抑制MCF-7细胞向CXCL12的迁移。我们还表明，二恶英在缺氧条件下降低CXCR4，在雌二醇诱导条件下降低MCF-7细胞中的CXCL12。最后，由于CXCR4/CXCL12轴与多种癌症的进展有关，我们鉴定了几种其他癌细胞系，其中二恶英调节CXCR4和CXCL12水平。因此，我们提出二恶英预防乳腺癌的一种机制可能是通过下调CXCR4和CXCL12，从而抑制疾病进展。此外，芳烃受体的其他无毒配体（选择性AHR调节剂）可能通过类似机制发挥其保护作用。
