Effectors of estrogen and tamoxifen actions in breast cancer cells.

Abstract

Estrogen receptor (ER) belongs to the nuclear receptor super family, and is a key regulator of proliferation and differentiation in normal mammary gland and breast cancer cells. It has been reported that steroid and xenobiotic receptor (SXR), a new member of nuclear receptors, is expressed in breast cancer cells. We investigated the role of SXR and found a series of novel actions. (I) tamoxifen (TAM) activated SXR-mediated transcription of cytochrome P-450 3A4 (CYP3A4) and multidrug resistance-1 (MDR-1) genes, which are involved in TAM metabolism. Thus, SXR may be involved in TAM resistance by decreasing its local concentration. (II) ER-mediated transcription was potentiated by SXR in a receptor-concentration dependent manner in MCF-7 cells. We then further investigated the mechanism of SXR action. SXR did not bind with ER or estrogen response element, and did not alter ER-coactivator binding. On the other hand, the binding between ER and silencing mediator of retinoid and thyroid receptors (SMRT) was decreased by SXR in a dose dependent manner. These results suggest that (III) SXR augmented the ER-mediated transcription, by squelching limiting amount of SMRT. These series of studies have shown that SXR expression in breast cancer may alter the sensitivity to estrogen and its related compounds. SXR may stimulate the development by potentiating estrogen action through ER. It may decrease the effect of TAM by facilitating its metabolism. Taken together, SXR may be an exacerbation factor of breast cancer. [J Physiol Sci. 2006;56 Suppl:S13]