In the lactating mammary gland, iodide is concentrated up to 36-fold in milk compared with the plasma iodide concentration, due to stimulation of the sodium/iodide symporter (NIS). Some hormone-dependent breast cancers also concentrate iodide, up to 7-fold, but iodide uptake in breast cancer must be enhanced to make radioiodine treatment possible, analagous to the TSH stimulation required for uptake of radioiodine into thyroid cancer. All-trans retinoic acid (RA) treatment stimulates iodide uptake, MS mRNA, and MS protein in MCF-7 cells, an estrogen receptor (ER) positive human breast cancer cell line, in a time and dose dependent fashion. No RA-induction of iodide uptake is seen in an ER-negative breast cancer cell line, MDA-MB 231, or a normal breast-derived cell line, MCF-12A. An in vitro clonogenic assay demonstrated selective toxicity of radioiodine following RA stimulation of MCF-7 cells. MCF-12A cells have abundant MS protein, but no functional iodide uptake. MS regulation differs significantly in the breast compared to the thyroid, and differs in normal breast and breast cancer cell lines. We propose to study the regulation of iodide transport in breast cancer cell lines compared to normal breast and thyroid cell lines, with the goals of optimzing iodide uptake and selectively targeting breast cancer cells.
Specific aims i nclude: 1. Determine the mechanism of RA-mediated transcriptional regulation of the NIS gene in breast-derived cells utilizing selective retinoid agonists and cell lines with a range of endogenous RAR and RXR expression. 2. To determine the characteristics of NIS protein expression, subcellular localization, and kinetics that are associated with maximal function of NIS in breast-derived cell lines and those features that distinguish functional iodide uptake among cell lines that express NIS protein. 3. Utilize an in vitro model to optimize RA-stimulated radiation-mediated cell killing in breast cancer cells. 4. Develop in vivo models to determine the efficacy and specificity of RA-stimulated iodide uptake into breast cancer and determine the influence of enhancers and radiation sensitizers. RA raioiodide uptake may be useful for diagnosis and treatment of some differentiated breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089364-04
Application #
6706290
Study Section
Special Emphasis Panel (ZRG1-REB (01))
Program Officer
Stone, Helen B
Project Start
2001-01-12
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2005-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$212,940
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Brent, Gregory A; Kogai, Takahiko (2013) Cancer: Novel target to enhance radioiodine uptake in thyroid cancer. Nat Rev Endocrinol 9:508-9
Kogai, Takahiko; Liu, Yan-Yun; Mody, Kaizeen et al. (2012) Regulation of sodium iodide symporter gene expression by Rac1/p38? mitogen-activated protein kinase signaling pathway in MCF-7 breast cancer cells. J Biol Chem 287:3292-300
Brent, Gregory A (2012) Mechanisms of thyroid hormone action. J Clin Invest 122:3035-43
Kogai, Takahiko; Brent, Gregory A (2012) The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer therapeutics. Pharmacol Ther 135:355-70
Kogai, Takahiko; Liu, Yan-Yun; Richter, Laura L et al. (2010) Retinoic acid induces expression of the thyroid hormone transporter, monocarboxylate transporter 8 (Mct8). J Biol Chem 285:27279-88
Brent, Gregory A (2010) The impact of perchlorate exposure in early pregnancy: is it safe to drink the water? J Clin Endocrinol Metab 95:3154-7
Brent, Gregory A (2010) Environmental exposures and autoimmune thyroid disease. Thyroid 20:755-61
Ohashi, Emi; Kogai, Takahiko; Kagechika, Hiroyuki et al. (2009) Activation of the PI3 kinase pathway by retinoic acid mediates sodium/iodide symporter induction and iodide transport in MCF-7 breast cancer cells. Cancer Res 69:3443-50
Kogai, Takahiko; Sajid-Crockett, Saima; Newmarch, Lynell S et al. (2008) Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells. J Endocrinol 199:243-52
Kogai, Takahiko; Ohashi, Emi; Jacobs, Megan S et al. (2008) Retinoic acid stimulation of the sodium/iodide symporter in MCF-7 breast cancer cells is mediated by the insulin growth factor-I/phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase signaling pathways. J Clin Endocrinol Metab 93:1884-92

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