Chapter 23 - Regulation and Enhancement of Endogenous Sodium Iodide Symporter Expression: NIS Regulatory Pathways in Thyroid and Breast Cancer

Abstract

The sodium iodide symporter (NIS) gene is expressed at a high level in the thyroid gland and the lactating breast. The difference in the factors that regulate NIS gene expression in thyroid and breast suggests that there are tissue-specific pathways involved. Thyroid-stimulating hormone, or thyrotropin (TSH) is the major regulator of NIS expression in the normal thyroid and also stimulates NIS in more than 80% of differentiated thyroid cancers. TSH stimulates NIS gene expression through the proximal promoter and the NIS far upstream enhancer (NUE). The goal in thyroid cancer treatment is to optimize iodine uptake. A number of different strategies and agents have been used to stimulate NIS expression and iodine uptake in refractory thyroid cancer, although TSH remains the most potent stimulus. Improved understanding of NIS regulatory pathways in thyroid and breast cancer should lead to additional therapeutic options. NIS gene regulation in lactating breast tissue and breast cancer has been partially characterized. Oxytocin, a critical regulator of NIS in lactating mammary glands, activates the cAMP/PKA pathway and/or the inositol triphosphate-Ca2+ pathway. 8-bromoadenosine-cAMP or endogenous cAMP inducer, IBMX, and cholera toxin increase NIS expression in MCF-7 breast cancer cells, demonstrating a role for the cAMP pathway in mammary gland NIS expression. Extensive experience with 131I treatment of thyroid cancer has demonstrated the importance of maximizing the magnitude of specific radioiodide uptake in tumors. The regulation of NIS expression in normal and malignant thyroid cells, therefore, has been widely investigated.