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Enhanced Expression of Adenovirus-Mediated Sodium Iodide Symporter Gene in MCF-7 Breast Cancer Cells with Retinoic Acid Treatment

¹ Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; ² Department of Nuclear Medicine, Armed Forces Capital Hospital, Seongnam, Korea; ³ Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea; ⁴ Department of Otolaryngology–Head and Neck Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; and ⁵ Institute for Biomacromolecules, University of Ulsan College of Medicine, Seoul, Korea

Correspondence: For correspondence or reprints contact: Dae Hyuk Moon, MD, Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, Korea. E-mail: dhmoon{at}amc.seoul.kr

Increased expression of the sodium iodide symporter (NIS) is required for effective radioiodine treatment and reporter gene imaging of breast cancer. We investigated the effect of retinoic acid on adenovirus-mediated expression of the human NIS gene in the MCF-7 breast cancer cell line. Methods: The MCF-7 cell line was infected with recombinant adenovirus carrying the human NIS gene (Rad-NIS). Levels of NIS messenger RNA (mRNA) and protein expression and radioiodine (¹²⁵I) uptake were measured to evaluate adenovirus-mediated NIS gene expression in wild-type and Rad-NIS–infected MCF-7 cells after treatment with all-trans-retinoic acid (ATRA; 10^–8–10^–6 mol/L). Results: The transduction efficiency of adenovirus in MCF-7 cells at a multiplicity of infection (MOI) of 50 was >60%. After incubation with 10^–6 mol/L ATRA, the mRNA level in Rad-NIS–infected MCF-7 cells increased to 118.5 times that of wild-type MCF-7 cells, whereas the mRNA level in wild-type MCF-7 cells showed only a 2.1-fold increase. Western blot, immunocytochemical staining, and flow cytometry analyses showed that NIS protein expression in MCF-7 cells infected with Rad-NIS increased after ATRA treatment. With ATRA treatment, the amount of ¹²⁵I uptake increased in a dose-dependent manner (P < 0.001). The ¹²⁵I uptake in wild-type MCF-7 cells increased 3.1-, 5.5-, and 7.6-fold with treatment with 10^–8, 10^–7, and 10^–6 mol/L ATRA, respectively. Rad-NIS–infected cells showed a 4.0-fold increase in ¹²⁵I uptake. Treatment of Rad-NIS–infected cells with 10^–8, 10^–7, and 10^–6 mol/L ATRA increased ¹²⁵I uptake by 4.9-, 8.2-, and 27.6-fold, respectively, compared with wild-type MCF-7 cells. The level of NIS expression in Rad-NIS–infected MCF-7 cells treated with 10^–6 mol/L ATRA (245.0 ± 13.7 pmol/10⁶ cells) was much greater than the sum of the expression levels seen in ATRA-treated wild-type cells and Rad-NIS–infected wild-type cells. Conclusion: Retinoic acid increases adenovirus-mediated NIS expression in MCF-7 cells. Our results indicate that improved efficiency of NIS gene therapy or reporter imaging in breast cancer may be possible with retinoic acid treatment.

Key Words: sodium iodide symporter • retinoic acid • adenovirus • MCF-7 • radioiodine

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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