After the disaster at the nuclear power plant at Chernobyl, more than 800 children who drank milk from exposed dairy herds developed thyroid cancers¹. The cancers were caused largely by exposure to radioactive fallout (most of which consisted of radioiodide, derived from iodine-131) in grass; the radioiodide was concentrated in the cows' mammary cells, secreted into their milk, ingested by children, and concentrated in the children's thyroid glands, causing cancer. This was a tragic consequence of the essential process of iodide transport into both thyroid and mammary cells. Transport of iodide into thyroid cells is mediated by a transmembrane carrier protein, the sodium– iodide symporter (NIS). Writing in Nature Medicine², Tazebay, Wapnir and colleagues show that the NIS is also responsible for iodide transport into epithelial cells of the normal lactating breast and breast cancer cells (Fig. 1). Their results may reopen the 60-year-old discussion of the possible use of iodide transport for detecting or treating breast cancer, and suggest a possible new way of treating thyroid cancer.

Figure 1: Expression of the sodium–iodide symporter (NIS) in breast tissue.

Tazebay et al.² have shown that lactating (a) and cancerous (b) breast tissues express the NIS.

High resolution image and legend (48K)

Iodinated compounds are essential for the normal growth and development of vertebrates. The thyroid gland actively accumulates iodide from the blood against an electrochemical gradient, and incorporates it into thyroxine and tri-idodothyronine hormones, which control the basal meta-bolic rates of many cells. It has been known for at least 60 years that the breast also concentrates iodide, secreting it into milk³. Nursing infants synthesize essential thyroid hormones using iodide from breast milk. Active transport of iodide into the thyroid is mediated by the NIS^{4, 5}, which simultaneously transports two different ions — sodium and iodide — in the same direction across the plasma membrane of thyroid cells. Tazebay et al.² now show that the NIS also concentrates iodide in normal lactating breast ducts.

During pregnancy and lactation, dramatic changes occur in the normal mammalian breast. During pregnancy, breast enlargement results from hormonally stimulated, rapid proliferation of epithelial cells of breast alveoli and ducts. The synthesis in the pituitary gland of the milk precursor protein prolactin also increases, peaking at birth with production of milk. Suckling further stimulates prolactin synthesis, leading to more milk production. Tazebay et al. find that the NIS protein is present in mammary tissue in mice just before birth and during lactation, but that NIS expression is significantly decreased at weaning. If suckling begins again, NIS levels rise, suggesting that NIS expression is hormonally regulated. Experimentally, a combination of oestrogen, oxytocin and prolactin — the hormones present during natural lactation — most effectively induces NIS expression in mammary tissues. In the breast-cancer cell line MCF-7, retinoic acid has also been shown to stimulate NIS expression and radioiodide uptake⁶.

The enormous burst of proliferation of breast epithelial cells during normal pregnancy and lactation is echoed by the abnormal cellular proliferation occurring in breast cancer. As shown by Tazebay et al., NIS is also expressed in the mammary tumours of mice whose cancers are caused by experimental overexpression of the oncogenes HER2/neu or ras. The authors find that mouse mammary tumours that express NIS — unlike those that do not express NIS, or normal, non-lactating mouse mammary glands — accumulate a radioactively labelled iodine substitute. It was reported some 25 years ago⁷ that human breast tumours (whether benign or invasive) take up more radioiodide than do normal breast epithelial cells. It seems that NIS may be responsible: 87% of the primary invasive human breast tumours analysed by Tazebay et al. expressed NIS, but none of the non-lactating breast tissue did.

The specific uptake of radioiodide through the NIS is invaluable in the diagnosis and treatment of both benign and malignant thyroid disorders. For example, radioiodide is commonly used to treat overactive thyroid glands, such as those seen in Graves' disease. Thyroid cancer cells generally retain their ability to transport iodide, although to a lesser extent than normal thyroid cells. So, for patients whose thyroids have been removed during treatment for thyroid cancer, whole-body radioiodide scanning is often used to detect cancerous cells of thyroid origin that have migrated (metastasized) to other sites in the body. Often during these clinical procedures, iodide uptake also occurs in other tissues such as salivary gland and lactating breast. This is consistent with the observation² that the NIS is expressed in some non-cancerous tissues near breast tumours. Administration of higher doses of radioiodide is an effective treatment for metastasized thyroid cancer.

The implications of the new findings² for diagnosing and treating breast cancer are uncertain, however. Unlike thyroid-cancer patients, most breast-cancer patients have functioning thyroids. Normal thyroid cells accumulate and retain iodide far more efficiently than do thyroid cancer cells, breast epithelial cells, or any other cell type⁸. The presence of a patient's normal thyroid will pose a challenge to the use of radioiodide to detect or treat breast tumours, as it will sequester nearly all the radioiodide until the thyroid itself is destroyed. Also, it is not yet known what proportion of human breast cancers express functional NIS and hence accumulate iodide. The results of Tazebay et al. indicate that the NIS may be incorrectly localized within the cells of some breast tumours and thus incapable of taking up iodide. So, more work is needed before we can know whether uptake of iodide in breast tumours will be of clinical use.

The results have greater implications for thyroid cancer patients. Treating such patients with radioiodide is effective when the radioiodide is retained in the cells; however, metastases can lose their ability to take up and accumulate radioiodide. In this case, thyroid cancers often develop further, and other treatments — such as external beam radiotherapy — are usually ineffective at stopping the disease. So there are intense efforts to try to stimulate such thyroid tumours to 'redifferentiate' and take up radioiodide again. Tazebay et al.² have shown that it is possible to use hormones to stimulate the expression of NIS in non-lactating mouse mammary cells. Perhaps it might be possible to stimulate thyroid metastases to express NIS in the same way, and hence to regain the ability to accumulate enough radioiodide for effective treatment.

References

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2. Tazebay, U. H. et al. Nature Med. 6, 871– 878 (2000).
3. Elmer, A. Iodine Metabolism and Function (Oxford Univ. Press, London, 1938).
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1. Piri L. Welcsh is in the Department of Medicine, Division of Medical Genetics, and David A. Mankoff is in the Department of Radiology, University of Washington, Seattle, Washington 98195, USA.

Correspondence to: Piri L. Welcsh¹ e-mail: Email: piri@u.washington.edu

Correspondence to: David A. Mankoff¹ e-mail: Email: dam@u.washington.edu