Tamoxifen activates CYP3A4 and MDR-1 genes through steroid and xenobiotic receptor in breast cancer cells.

点击翻译按钮获取中文摘要

Cytochrome P450 monooxygenase 3A4 (CYP3A4) is responsible for the metabolism of endogenous steroids, prescribed drugs and xenobiotics. P-glycoprotein, encoded by multidrug resistance 1 (MDR1) gene, functions as an efflux pump transporting substances from inside of the intestinal cells to the lumen to be absorbed or eliminated. Both genes are regulated by steroid and xenobiotic receptor (SXR), a member of nuclear hormone receptor superfamily. Various endogeneous steroids and drugs function as ligands of SXR. Although CYP3A4, MDR1 and SXR are expressed mainly in the liver and the small intestine, these genes are also expressed in breast cancer cells such as MCF-7 cells. Since tamoxifen (TAM), an antiestrogen used for breast cancer treatment, may be involved in SXR-mediated transcription and is known to be metabolized by CYP3A4 and P-glycoprotein, we investigated the effect of TAM on these SXR targeted genes in breast cancer cell lines. Transient transfection-based reporter gene assays showed 4-hydroxy TAM as well as TAM activated the SXR-mediated transcription through CYP3A4 and MDR1 promoters in a ligand- and receptor concentration-dependent manner. We confirmed the binding of 4-hydroxy-TAM to SXR by ligand binding assay. Moreover, semi-quantitative RT-PCR studies revealed that 4-hydroxy TAM activated the expression of CYP3A4 and MDR1 mRNA in MCF-7 cells. These results suggest that TAM induces CYP3A4 and MDR1 gene expression through SXR, which reduces TAM concentration in breast cancer cells. Thus, the expression of SXR in breast cancer cells could be a potential risk factor, which may induce local TAM resistance.