The effect of endocrine-disrupting chemicals on development of breast cancer.

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It has been reported that steroid and xenobiotic receptor (SXR) is expressed in a series of breast cancer cell lines. SXR is ligand-activated transcription factor, which activates transcription through a responsive element conserved in the promoter of the cytochrome P450 (CYP) isoforms. The CYP3A4 enzymes are known to be involved in the metabolism of a wide range of xenobiotics, natural and synthetic steroids, and antisteroids, including tamoxifen (TAM). in the present study, we investigated the transcriptional regulation of CYP3A4 by SXR using transient transfection-based reporter assays in the absence band presence of ligand, such as TAM and PCB. The expression plasmid encoding SXR was cotransfected with reporter plasmid XREM-CYP3A4-Luc in MCF-7 cells, which are ER-and SXR-positive human breast cancer cell lines. These cells were treated with different concentrations of TAM and PCB (4(OH)-2',3,3',4',5'-penta chrolo biphenyl). In MCF-7 cells, 10^<-8> M TAM increased the CYP3A4 transcriptional activity, compared to 10^<-6>M TAM in CV-1, fibroblast cells. TAM and PCB activated SXR-mediated transcription of CYP3A4 in ligand and SXR dose-dependent manners. These results suggest that the induction of CYP3A4 by tamoxifen and PCB might be involved in the resistance to tamoxifen in breast cancer, and the risk of breast cancer.