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Tazebay

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

Alotaibi H, Yaman EC, Demirpence E, Tazebay UH.

Biochem Biophys Res Commun. 2006 Jul 14;345(4):1487-96. Epub 2006 May 15.

"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-alpha (ERalpha) positive cells and we investigated the role of ERalpha in the regulation of NIS expression. We showed that the suppression of endogenous ERalpha by RNA interference downregulates NIS expression in ERalpha positive mammary cells. Besides, in an ERalpha negative cell line, reintroduction of ERalpha 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 ERalpha and mediates ERalpha-dependent activation of transcription. Our results indicate that unliganded ERalpha (apo-ERalpha) contributes to the regulation of NIS gene expression."

The mammary gland iodide transporter is expressed during lactation and in breast cancer.

Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RG, Carrasco N.

Nat Med. 2000 Aug;6(8):871-8.

"The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer."

"Besides the thyroid, active iodide transport occurs in the lactating mammary gland, salivary glands and gastric mucosa.  Iodide concentrated in lactating mammary gland and secreted into milk is used by the nursing newborn for the biosynthesis of thyroid hormones.... The mammary gland iodide transporter was the essential link in the chain of events that led to a higher thyroid cancer incidence in the aftermath of the Chernobyl power plant accident.  I-131 in radioactive fallout was accumulated by cattle in milk, and children who ingested I-131 contaminated milk subsequently concentrated I-131 in their thyroids through the thyroid NIS, exposing the gland to tumorigenic doses of radiation."

"Effects of hormones on mgNIS [mammary gland NIS] expression in ovariectomized mice.  We administered 17-B-estradiol, progesterone, oxytocin, and prolactin, both individually and in different combinations, to nubile ovariectomized adult mice and assessed mgNIS expression in mammary tissue.  Administration of oxytocin alone to ovariectomized mice did not cause an increase in mgNIS expression.... Of all the hormones tested individually, only 17-B-estradiol led to a clearly discernible increase in mgNIS expression.... The upregulating effect of oxytocin on mgNIS expression may require estrogen.

"The greatest increase in mgNIS expression occurred after administration of 17-B-estradiol, oxytocin and prolactin together.... When progesterone was added to the 17-B-estradiol-oxytocin-prolactin combination, mgNIS expression was substantially decreased.  Conversely, a comparison of mgNIS expression in mice treated with estrogen or estrogen plus progesterone showed that progesterone did not interfere with 17-B-estradiol enhancement of mgNIS expression.  In conclusion, the combination of estrogen, prolactin and oxytocin (in the absence of progesterone) led to the highest levels of mgNIS expression in ovariectomized mice.  This combination of hormones closely resembles the relative hormonal levels in mice and rats during lactation."

"More than 80% of the breast cancer specimens analyzed expressed mgNIS, in contrast to no expression in normal tissues from reductive mammoplasties, indicating that mgNIS is unregulated with a high frequency during malignant transformation in human breast."

"A threshold level of circulating estrogens seemed to be necessary for optimal mgNIS expression overall, and in particular for the upregulation of mgNIS by oxytocin.  The cooperative function of estrogens in the effect of oxytocin on mgNIS may be explained by the likelihood that oxytocin receptor mRNA is upregulated by estrogen in the breast, as it is in the hypothalamus and uterus.  Additionally, estrogen may have a direct effect on mgNIS transcription, as the NIS promoter contains several half-site estrogen-responsive elements."

"In intact, nongestational, nonlactating animals, exogenous prolactin would cause endogenous estrogen levels, which are lower than those in gestational or lactating animals, to decrease below the threshold, preventing concomitantly administered oxytocin from stimulating mgNIS expression.... In the presence of high levels of estrogen, prolactin may have a separate direct or indirect stimulatory effect on mgNIS expression by an as yet unknown mechanism.... During lactation, estrogens would remain above the necessary threshold for oxytocin to stimulate mgNIS expression and for prolactin to enhance, rather than antagonize, this effect.... The ability of progesterone to inhibit the combined stimulatory effect of 17-B-Estradiol, oxytocin and prolactin on mgNIS expression may involve a direct inhibition of oxytocin receptor signaling by competitive binding of progesterone to the oxytocin receptor in the breast, similar to progesterone's effect in the uterus."

"mgNIS expression may also be induced by nonhormonal factors involved in the malignant transformation of mammary epithelial cells."

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