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Signaling through 3',5'-Cyclic Adenosine Monophosphate and Phosphoinositide-3 Kinase Induces Sodium/Iodide Symporter Expression in Breast Cancer

Departments of Veterinary Biosciences (K.A.B.K., C.C.C.), Veterinary Clinical Sciences (W.C.K.), and Physiology and Cell Biology (S.M.J.), The Ohio State University, Columbus, Ohio 43210; Department of Biochemistry (J.-Y.C.), School of Dentistry, Kyungpook National University, Daegu 700-42, Republic of Korea; Department of Biological Sciences (K.-Y.R.), Stanford University, Stanford, California 94305; Department of Biological Chemistry (X.L.), University of California, Irvine, Irvine, California 92697; Department of Microbiology and Immunology (J.A.M.), East Carolina University School of Medicine, Greenville, North Carolina 27858; Center for Vascular Biology (T.H.), University of Connecticut Health Center, Farmington, Connecticut 06030; Department of Molecular Genetics, Microbiology, and Immunology (C.H.L.), University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854; Department of Oncology and Neurosciences (E.D.C.), "G. d’Annunzio" University, 66100 Chieti, Italy; Department of Pharmacology (R.K.), Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106; Department of Molecular and Cellular Biology (M.Z.), Baylor College of Medicine, Houston, Texas 77030; and Division of Laboratory Animal Resources (D.Y.H.), National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul 122-704, Republic of Korea

Address all correspondence and requests for reprints to: Sissy M. Jhiang, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, Ohio 43210. E-mail: jhiang.1{at}osu.edu.

The sodium/iodide symporter (NIS) is a membrane transport glycoprotein normally expressed in the thyroid gland and lactating mammary gland. NIS is a target for radioiodide imaging and therapeutic ablation of thyroid carcinomas and has the potential for similar use in breast cancer treatment. To facilitate NIS-mediated radionuclide therapy, it is necessary to identify signaling pathways that lead to increased NIS expression and function in breast cancer. We examined NIS expression in mammary tumors of 14 genetically engineered mouse models to identify genetic manipulations associated with NIS induction. The cAMP and phosphoinositide-3 kinase (PI3K) signaling pathways are associated with NIS up-regulation. We showed that activation of PI3K alone is sufficient to increase NIS expression and radioiodide uptake in MCF-7 human breast cancer cells, whereas cAMP stimulation increases NIS promoter activity and NIS mRNA levels but is not sufficient to increase radioiodide uptake. This study is the first to demonstrate that NIS expression is induced by cAMP and/or PI3K in breast cancer both in vivo and in vitro.

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