Roles of steroid and xenobiotic receptor (SXR) on ER-mediated transcription in breast cancer cells

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The estrogen receptor (ER) is a key regulator of proliferation and differentiation in breast cancer cells. Steroid and xenobiotic receptor (SXR) is highly expressed in the liver and small intestine and regulates the expression of cytochrome P450 monooxygenase 3A4 (CYP3A4) and P-glycoprotein (P-gp) that is encoded by multidrug resistance 1 (MDR1) gene. SXR is also expressed in normal and neoplastic breast tissue. In the present study, the effect of steroid and xenobiotic receptor (SXR) on 17.-estradiol (E)-induced 2 transcription through ER. was studied. SXR augmented ER-mediated transcription in the presence of E in MCF-7 breast cancer-derived cells and CV-1 fibroblast-derived cells. SXR did not directly bind to ER. or ERE 2in vitro, indicating that SXR may affect ER-mediated transcription by altering cofactor biding to ER. Although SXR did not alter the binding between ER. and p300/CBP interacting protein (p/CIP), it decreased the binding of a specific corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT) to liganded ER. as assessed by mammalian two-hybrid, GST pull down, immunoprecipiation and newly developed Liquid Chemiluminescent DNA Pull Down Assays. These results indicate that SXR augmented ER-mediated transcription by dissociating SMRT from ER. Thus, the expression of SXR in breast cancer cells may alter the ER signaling, which may play crucial role for growth and differentiation of breast cancer cells. We performed realtime quantitative RT-PCR studies using SXR promoter. The expression of SXR mRNA was increased in those cases ER positive, PgR positive, HER2 negative, without node metastasis, and low grade.