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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.