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

雌激素受体（ER）是乳腺癌细胞增殖和分化的关键调节因子。以前的研究表明，它的作用可能受到其他核因子的调节。一种这样的候选物可以是在肿瘤性乳腺组织中表达的类固醇和异生素受体（SXR）。本实验研究了SXR对17-雌二醇（E_2）通过雌激素受体诱导的转录的影响。在E_2存在下，SXR增强了MCF-7乳腺癌细胞和CV-1成纤维细胞ER介导的转录。另一方面，SXR单独不影响CV-1细胞中含雌激素反应元件（ERE）的启动子活性。SXR在体内和体外均不直接与ER和ERE结合，表明SXR可能通过改变与ER结合的辅因子来影响ER介导的转录。尽管SCR并不改变ER与p300/CBP相互作用蛋白（p/CIP）的结合，但通过哺乳动物双杂交、GST pull down和新开发的液相荧光DNA pull down分析，SCR降低了一种特异性辅阻遏物--类维生素A和甲状腺激素受体沉默介体（SMRT）与配体ER的结合。这些结果表明，SXR通过抑制SMRT增强ER介导的转录。因此，SXR在乳腺癌细胞中的表达可能改变ER信号，这可能对乳腺癌细胞的生长和分化起关键作用。

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.