Enhancement of sodium/iodide symporter expression in thyroid and breast cancer

Abstract

The sodium/iodide symporter (NIS) mediates iodide uptake in the thyroid gland and lactating breast. NIS mRNA and protein expression are detected in most thyroid cancer specimens, although functional iodide uptake is usually reduced resulting in the characteristic finding of a 'cold' or non-functioning lesion on a radioiodine image. Iodide uptake after thyroid stimulating hormone (TSH) stimulation, however, is sufficient in most differentiated thyroid cancer to utilize b-emitting radioactive iodide for the treatment of residual and metastatic disease. Elevated serum TSH, achieved by thyroid hormone withdrawal in athyreotic patients or after recombinant human thyrotropin administration, directly stimulates NIS gene expression and/or NIS trafficking to the plasma membrane, increasing radioiodide uptake. Approximately 10-20% differentiated thyroid cancers, however, do not express the NIS gene despite TSH stimulation. These tumors are generally associated with a poor prognosis. Reduced NIS gene expression in thyroid cancer is likely due in part, to impaired trans-activation at the proximal promoter and/or the upstream enhancer. Basal NIS gene expression is detected in about 80% breast cancer specimens, but the fraction with functional iodide transport is relatively low. Lactogenic hormones and various nuclear hormone receptor ligands increase iodide uptake in breast cancer cells in vitro, but TSH has no effect. A wide range of 'differentiation' agents have been utilized to stimulate NIS expression in thyroid and breast cancer using in vitro and in vivo models, and a few have been used in clinical studies. Retinoic acid has been used to stimulate NIS expression in both thyroid and breast cancer. There are similarities and differences in NIS gene regulation and expression in thyroid and breast cancer. The various agents used to enhance NIS expression in thyroid and breast cancer will be reviewed with a focus on the mechanism of action. Agents that promote tumor differentiation, or directly stimulate NIS gene expression, may result in iodine concentration in 'scan-negative' thyroid cancer and some breast cancer.

The Effect of Tanespimycin (17-AAG) on Radioiodine Accumulation in Sodium-Iodide Symporter Expressing Cells

“…Increased accumulation of iodide in the cells is primarily attributable to increased iodide influx, but is also affected by iodide efflux [5]. Previously, some chemicals that might induce an increase in the accumulation of radioiodine in thyroid cells via enhanced iodide intake, or reduced iodine efflux from cells, have been identified.…”

“…Interest in NIS has, therefore, risen with regard to the possibility of using it in the treatment and diagnosis of breast cancer [5,6]. However, thyroid tumors gradually lose the expression of differentiation genes, including NIS, during the dedifferentiation process [7].…”

“…Certain chemicals and drugs have been reported to enhance radioiodine accumulation in thyroid and thyroid cancer cells [5,8]. Among them, tanespimycin-previously referred to as 17-AAG (17-allylamino-17-demethoxygeldanamycin)-is considered to be one of the promising agents.…”

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

“…Use of therapeutic radioisotope ( 131 I) in these circumstances was associated with an increased cytotoxic effect. Selective cytotoxicity of 131 I was significantly increased from approximately 17% in MCF-7 cells treated with ATRA alone to 80% in MCF-7 cells treated with Dex in the presence of ATRA [120]. Combined treatment with ATRA/dexamethasone in vivo was associated with significant 123 I accumulation in MCF-7 xenografts that, by ex vivo gamma counting, revealed a 3.3-fold increase in iodide accumulation as compared to control tumours treated with ATRA alone.…”

Cholangiocarcinoma: from molecular biology to treatment

“…NIS has a key role in metabolic radiotherapy, using iodine-131, for the treatment of thyroid tumors, being also currently under active investigation for the treatment of extrathyroidal tumors. This means that NIS overexpression opens a new possibility of treatment for CC [26,[28][29][30][31].…”