The novel mechanism of the potentiation of estrogen action by steroid and xenobiotic receptor (SXR) in breast cancer cells.

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Estrogen receptor (ER) is a key regulator of proliferation and differentiation in breast cancer cells. Previous studies have shown that its action may be modulated by other nuclear factors. One such candidate may be steroid and xenobiotic receptor (SXR) that is expressed in neoplastic breast tissue. In the present study, the effect of SXR on 17-estradiol (E_2)-induced transcription through ER was studied. SXR augmented ER-mediated transcription in the presence of E_2 in MCF-7 breast cancer-derived cells and CV-1 fibroblast-derived cells. On the other hand, SXR alone did not affect the estrogen response element (ERE)-containing promoter activity in CV-1 cells. SXR did not directly bind to ER nor ERE in vivo and in vitro, indicating that SXR may affect ER-mediated transcription by altering cofactor binding to ER. Although SCR 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 by mammalian two-hybrid, GST pull down and a newly developed liquid fluorescence DNA pull down assays. These results indicate that SXR augmented ER-mediated transcription by squelching SMRT. 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.