Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

The function of sodium iodide symporter (Na+/I− symporter, or NIS) in mammary epithelial cells is essential for the accumulation of I− in milk; the newborn’s first source of I− for thyroid hormone synthesis. Furthermore, increased mammary gland NIS expression has previously been shown in human breast cancer. Several hormones and factors including all-trans-retinoic acid (tRA) regulate the expression of NIS. In this study, using breast cancer cell lines, we established that tRA-responsive NIS expression is confined to estrogen receptor-α (ERα) positive cells and we investigated the role of ERα in the regulation of NIS expression. We showed that the suppression of endogenous ERα by RNA interference downregulates NIS expression in ERα positive mammary cells. Besides, in an ERα negative cell line, reintroduction of ERα resulted in the expression of NIS in a ligand-independent manner. We also identified a novel estrogen-responsive element in the promoter region of NIS that specifically binds ERα and mediates ERα-dependent activation of transcription. Our results indicate that unliganded ERα (apo-ERα) contributes to the regulation of NIS gene expression.