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Differential Regulation of Sodium/Iodide Symporter Gene Expression by Nuclear Receptor Ligands in MCF-7 Breast Cancer Cells

Molecular Endocrinology Laboratory (T.K., Y.K., A.I.L., L.H.C., E.O., K.T., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, Departments of Medicine and Physiology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California 90073; Vitae Pharmaceuticals (R.A.C.), Irvine, California 92618; and Third Department of Medicine (K.T., T.S.), Yamanashi University, Yamanashi 409-3898, Japan

Address all correspondence and requests for reprints to: Dr. Gregory A. Brent, Molecular Endocrinology Laboratory, Building 114, Room 230, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: gbrent{at}ucla.edu.

The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of ß-emitting radioiodide-131 (¹³¹I) in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance ¹³¹I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) ß/ produced marked NIS induction; and selective stimulation of RAR, RAR, or retinoid X receptor produced more modest induction. Maximal NIS induction was seen with 9-cis retinoic acid and AGN190168, a RAR ß/-agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC₅₀ of tRA for NIS stimulation to approximately 7%, such that 10 ^–7 M tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of ¹³¹I greater than 10^–6 M tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 d) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis retinoic acid/Dex. The addition of Dex reduced the effective dose of retinoid and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of ¹³¹I after combination treatment.

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