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

¹ Department of Surgery, ² Division of Nuclear Medicine, and ³ Department of Pathology, Stanford University School of Medicine, Stanford, California; ⁴ Department of Radiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey; and ⁵ Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York

ABSTRACT

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.

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