Orsolya Dohán

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

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.

Advances in Na+/I− symporter (NIS) research in the thyroid and beyond

The Na(+)/I(-) symporter (NIS) is a plasma membrane glycoprotein that mediates active iodide uptake in the thyroid-the essential first step in thyroid hormone biosynthesis-and in other tissues, such as salivary and lactating mammary glands. Thyroidal radioiodide uptake has been used for over 60 years in the diagnosis and effective treatment of thyroid cancer and other diseases. However, the NIS cDNA was only isolated in 1996 by expression cloning in Xenopus laevis oocytes, marking the beginning of the molecular characterization of NIS and the study of its regulation, both in the thyroid and other tissues. One of the most exciting current areas of NIS research-radioiodide treatment of extrathyroidal cancers-was launched by the discovery of functional expression of endogenous NIS in breast cancer and by the ectopic transfer of the NIS gene into otherwise non NIS-expressing cancers. This review summarizes the main findings in NIS research, emphasizing the most recent developments.

The Na/I - Symporter Mediates Iodide Uptake in Breast Cancer Metastases and Can Be Selectively Down-Regulated in the Thyroid

Purpose: The Na+/I− symporter (NIS) is a key plasma membrane protein that mediates active iodide (I−) transport in the thyroid, lactating breast, and other tissues. Functional NIS expression in thyroid cancer accounts for the longstanding success of radioactive iodide (131I) ablation of metastases after thyroidectomy. Breast cancer is the only other cancer demonstrating endogenous functional NIS expression. Until now, NIS activity in breast cancer metastases (BCM) was unproven. Experimental Design: Twenty-seven women were scanned with 99mTcO4− or 123I− to assess NIS activity in their metastases. An 131I dosimetry study was offered to patients with I−-accumulating tumors. Selective down-regulation of thyroid NIS was tested in 13 patients with T3 and in one case with T3 + methimazole (MMI; blocks I− organification). NIS expression was evaluated in index and/or metastatic tumor samples by immunohistochemistry. Results: I− uptake was noted in 25% of NIS-expressing tumors (two of eight). The remaining cases did not show NIS expression or activity. Thyroid I− uptakes were decreased to ≤2.8% at 24 h in T3-treated patients and 1/100 normal with T3/MMI. Uptake (2.9%) was calculated in a peribronchial metastasis on 131I dosimetry scans at 4 h with disappearance of the signal by 24 h. We estimated a therapeutic dose of 3000 cGy could be achieved in this metastasis with 100 mCi of 131I if the tumor exhibited the same dynamics as the T3/MMI-suppressed thyroid. Conclusions: This is the first article of in vivo, scintigraphically detected, NIS-mediated I− accumulation in human BCM. T3/MMI down-regulation of thyroid NIS makes 131I-radioablation of BCM possible with negligible thyroid uptake and radiation damage.

Journey of the iodide transporter NIS: from its molecular identification to its clinical role in cancer

The Na+/I- symporter (NIS) is an intrinsic plasma membrane protein that mediates the active transport of I- in the thyroid, lactating mammary gland, stomach and salivary glands. The presence of NIS in the thyroid is exploited in diagnostic scintigraphic imaging and radioiodide therapy in thyroid cancer. The continued rapid progress in NIS research (aimed at the elucidation of the Na+-dependent I- transport mechanism, the analysis of NIS structure-function relations and the study of the tissue-specific regulation of NIS at all levels), holds potentially far-reaching medical applications beyond thyroid disease, in breast cancer and malignancies in other tissues.

Molecular Study of the Sodium–Iodide Symporter (NIS): A New Field in Thyroidology

The active transport of iodide into the thyroid is mediated by the Na(+)-I- symporter (NIS), an intrinsic membrane protein. NIS plays key roles in thyroid pathophysiology as the route by which I- reaches the gland for thyroid hormone biosynthesis, and as a means for diagnostic scintigraphic imaging and for radioiodide therapy in thyroid cancer. The molecular characterization of NIS started with the isolation in 1996 of a cDNA encoding rat NIS, and has subsequently led to a virtually new field in thyroidology. The research reviewed in this article clearly has far-reaching implications in the areas of structure/function of transport proteins, thyroid pathophysiology, hormone action mechanisms, cell differentiation and cancer.

Expression of the Na+/l-symporter (NIS) is markedly decreased or absent in gastric cancer and intestinal metaplastic mucosa of Barrett esophagus

BackgroundThe sodium/iodide symporter (NIS) is a plasma membrane glycoprotein that mediates iodide (I-) transport in the thyroid, lactating breast, salivary glands, and stomach. Whereas NIS expression and regulation have been extensively investigated in healthy and neoplastic thyroid and breast tissues, little is known about NIS expression and function along the healthy and diseased gastrointestinal tract.MethodsThus, we investigated NIS expression by immunohistochemical analysis in 155 gastrointestinal tissue samples and by immunoblot analysis in 17 gastric tumors from 83 patients.ResultsRegarding the healthy Gl tract, we observed NIS expression exclusively in the basolateral region of the gastric mucin-producing epithelial cells. In gastritis, positive NIS staining was observed in these cells both in the presence and absence of Helicobacter pylori. Significantly, NIS expression was absent in gastric cancer, independently of its histological type. Only focal faint NIS expression was detected in the direct vicinity of gastric tumors, i.e., in the histologically intact mucosa, the expression becoming gradually stronger and linear farther away from the tumor. Barrett mucosa with junctional and fundic-type columnar metaplasia displayed positive NIS staining, whereas Barrett mucosa with intestinal metaplasia was negative. NIS staining was also absent in intestinalized gastric polyps.ConclusionThat NIS expression is markedly decreased or absent in case of intestinalization or malignant transformation of the gastric mucosa suggests that NIS may prove to be a significant tumor marker in the diagnosis and prognosis of gastric malignancies and also precancerous lesions such as Barrett mucosa, thus extending the medical significance of NIS beyond thyroid disease.

Mechanism of anion selectivity and stoichiometry of the Na+/I- symporter (NIS)

I- uptake in the thyroid, the first step in thyroid hormone biosynthesis, is mediated by the Na+/I- symporter (NIS) with an electrogenic 2Na+ : 1I- stoichiometry. We have obtained mechanistic information on NIS by characterizing the congenital I- transport defect-causing NIS mutant G93R. This mutant is targeted to the plasma membrane but is inactive. Substitutions at position 93 show that the longer the side chain of the neutral residue at this position, the higher the Km for the anion substrates. Unlike WT NIS, which mediates symport of Na+ and the environmental pollutant perchlorate electroneutrally, G93T/N/Q/E/D NIS, strikingly, do it electrogenically with a 2∶1 stoichiometry. Furthermore, G93E/Q NIS discriminate between anion substrates, a discovery with potential clinical relevance. A 3D homology model of NIS based on the structure of the bacterial Na+/galactose transporter identifies G93 as a critical player in the mechanism of the transporter: the changes from an outwardly to an inwardly open conformation during the transport cycle use G93 as a pivot.

Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration: a 2-yr follow-up study.

We investigated the natural course of subclinical thyroid dysfunctions in geriatric patients, especially regarding their association with mortality rate. Ninety-three randomly selected chronically ill geriatric patients 64–87 (median: 77) yr of age participated in the screening study with a 2-yr follow-up. Serum thyrotropin (thyroid-stimulating hormone [TSH]), free thyroxine, triiodothyronine, and antibodies against thyroid peroxidase were measured. During the follow-up, patients with suppressed TSH levels who were otherwise euthyroid (untreated) had a higher mortality rate than patients with normal TSH (5/8 vs 18/64; p<0.05). The initial clinical state of these two subgroups did not differ significantly. Two-thirds of patients with treated hyperthyroidism died. The mortality rate of patients with initially subnormal but not suppressed TSH level was average and did not differ statistically from either the euthyroid or the hyperthyroid groups. Only 1 of 13 euthyroid patients with positive thyroid antibody titers developed a subsequent subclinical hypothyroidism. Subclinical hyperthyroidism was found to be associated with a higher mortality rate in chronically ill geriatric patients, which justifies screening for thyroid dysfunction and treatment of subclinical hyperthyroidism. In addition, a subnormal but measurable TSH was not indicative regarding the future development of hyperthyroidism. Finally, during the 2-yr follow-up, antibody positivity in the euthyroid cases did not prove to be predictive for the subsequent development of hypothyroidism.

Diagnosis from Thyroid Aspirates

OBJECTIVE: When fine needle aspiration cytology (FNA) of the thyroid is performed as a first-line test, the cytopathologist cannot be fully informed about the patients data. The authors investigated whether this decreases the accuracy of FNA and results in consequences for the patient. STUDY DESIGN: FNA smears of 202 patients, 190 with benign and 12 with malignant thyroid disease, were reevaluated, supplying the cytopathologist first with only information from the case history known already at the initial admission, and subsequently with full data. RESULTS: The FNA diagnoses were corrected in 13 cases; in 8/13 they showed a more serious finding. The therapeutic modality was changed in only one case. No corrections were made in the ultimately malignant cases. CONCLUSION: In several cases the cytopathologist may be handicapped by receiving only partial information about the patient, but in our patients this had no demonstrable adverse consequences. Thus, FNA can be performed upon patients admission.