The Na symporter (NIS) is a plasma membrane protein that mediates active I- transport in the thyroid and other tissues, including salivary glands, gastric mucosa, and lactating mammary glands (MG). NIS is regulated differently in each tissue. NIS-mediated I- transport in the thyroid is the first step in thyroid hormone biosynthesis. Endogenous functional expression of NIS in thyroid cancer is the foundation for the single most effective and most side effect-free anti-cancerous targeted radiation therapy available, i.e. radioiodide therapy, which has been successfully used in thyroid cancer for over 60 years. Our group isolated the cDNA encoding NIS and generated anti-NIS Abs. We have characterized thyroid NIS and its regulation. Mammary gland NIS (mgNIS) mediates active I- transport in lactating mammary cells, from which I- is passively translocated via a different transporter to the milk. mgNIS is expressed in lactating (but not in non-lactating) MG. mgNIS is regulated by estrogen, prolactin, and oxytocin. Mammary adenocarcinomas in transgenic mice display mgNIS-mediated active I- uptake. The only two cancers in which endogenous functional NIS is expressed are thyroid cancer and breast cancer. Over 80% of human breast cancers express mgNIS, but it is still unknown in what percentage of these NIS is functional. Normal non-lactating human breast samples do not express mgNIS. The endogenous expression of NIS in breast cancer provides an immense advantage over other cancers, into some of which NIS has been ectopically expressed by virus-mediated gene transfer. To characterize mgNIS in mammary cells and ascertain its potential value in breast cancer diagnosis and treatment, we propose: 1. a) To characterize the regulation of mgNIS in mammary cell lines; b) to investigate the effects of systemic and local regulatory factors on the expression of mgNIS in vivo; c) to determine whether low temperature and chemical chaperones promote targeting of mgNIS to the plasma membrane; d) to complement our understanding of I- translocation in the lactating mammary gland by assessing the role of putative apical I- transporters. 2) To develop a radioiodide therapeutic protocol and assess its effectiveness in the treatment of adenocarcinomas in animal models. 3) To ascertain, in fine needle aspirates from both human primary breast tumors and metastases, the functional expression of mgNIS and its possible correlation with other breast cancer parameters.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Endocrinology Study Section (END)
Program Officer
Stone, Helen B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Schools of Medicine
United States
Zip Code
Paroder-Belenitsky, Monika; Maestas, Matthew J; Dohán, Orsolya et al. (2011) Mechanism of anion selectivity and stoichiometry of the Na+/I- symporter (NIS). Proc Natl Acad Sci U S A 108:17933-8
Nicola, Juan Pablo; Basquin, Cécile; Portulano, Carla et al. (2009) The Na+/I- symporter mediates active iodide uptake in the intestine. Am J Physiol Cell Physiol 296:C654-62
Riesco-Eizaguirre, Garcilaso; Rodriguez, Irene; De la Vieja, Antonio et al. (2009) The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res 69:8317-25
Roepke, Torsten K; King, Elizabeth C; Reyna-Neyra, Andrea et al. (2009) Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis. Nat Med 15:1186-94
Reed-Tsur, Mia D; De la Vieja, Antonio; Ginter, Christopher S et al. (2008) Molecular characterization of V59E NIS, a Na+/I- symporter mutant that causes congenital I- transport defect. Endocrinology 149:3077-84
Dohan, Orsolya; Portulano, Carla; Basquin, Cecile et al. (2007) The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate. Proc Natl Acad Sci U S A 104:20250-5
De la Vieja, Antonio; Reed, Mia D; Ginter, Christopher S et al. (2007) Amino acid residues in transmembrane segment IX of the Na+/I- symporter play a role in its Na+ dependence and are critical for transport activity. J Biol Chem 282:25290-8
Dohan, Orsolya; De la Vieja, Antonio; Carrasco, Nancy (2006) Hydrocortisone and purinergic signaling stimulate sodium/iodide symporter (NIS)-mediated iodide transport in breast cancer cells. Mol Endocrinol 20:1121-37
Paroder, Viktoriya; Spencer, Shelly R; Paroder, Monika et al. (2006) Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT. Proc Natl Acad Sci U S A 103:7270-5