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Dexamethasone Stimulation of Retinoic Acid-Induced Sodium Iodide Symporter Expression and Cytotoxicity of 131-I in Breast Cancer Cells

Department of Internal Medicine II (S.U., M.J.W., N.C., M.S., B.G., C.S.), Ludwig-Maximilians-University, 81377 Munich, Germany; and Department of Endocrinology (J.C.M.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Christine Spitzweg, M.D., Klinikum Grosshadern, Medizinische Klinik II, Marchioninistrasse 15, 81377 Muenchen, Germany. E-mail: christine.spitzweg{at}med.uni-muenchen.de.

Context: The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as lactating breast tissue. Recently induction of functional NIS expression was reported in the estrogen receptor-positive human breast cancer cell line MCF-7 by all-trans retinoic acid (atRA) treatment in vitro and in vivo, which might offer the potential to treat breast cancer with radioiodine.

Objective: In the current study, we examined the effect of dexamethasone (Dex) on atRA-induced NIS expression and therapeutic efficacy of 131-I in MCF-7 cells.

Design: For this purpose, NIS mRNA and protein expression levels in MCF-7 cells were examined by Northern and Western blot analysis after incubation with Dex (10^–9 to 10^–7 M) in the presence of atRA (10^–6 M) as well as immunostaining using a mouse monoclonal human NIS-specific antibody. In addition, NIS functional activity was measured by iodide uptake and efflux assay, and in vitro cytotoxicity of 131-I was examined by in vitro clonogenic assay.

Results: After incubation with Dex in the presence of atRA, NIS mRNA levels in MCF-7 cells were stimulated up to 11-fold in a concentration-dependent manner, whereas NIS protein levels increased up to 16-fold and iodide accumulation was stimulated up to 3- to 4-fold. Furthermore, iodide efflux was modestly decreased after stimulation with Dex in the presence of atRA. Furthermore, in the in vitro clonogenic assay, selective cytotoxicity of 131-I was significantly increased from approximately 17% in MCF-7 cells treated with atRA alone to 80% in MCF-7 cells treated with Dex in the presence of atRA.

Conclusion: Treatment with Dex in the presence of atRA significantly increases functional NIS expression levels in addition to inhibiting iodide efflux, resulting in an enhanced selective killing effect of 131-I in MCF-7 breast cancer cells.

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