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Activation of the PI3 Kinase Pathway By Retinoic Acid Mediates Sodium/Iodide Symporter Induction and Iodide Transport in MCF-7 Breast Cancer Cells

¹ Molecular Endocrinology Laboratory, VA Greater Los Angeles Healthcare System, Departments of Medicine and Physiology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California and ² School of Biomedical Science, Tokyo Medical and Dental University, Kanda-Surugadai, Chiyoda-ku, Tokyo, Japan

Requests for reprints: Gregory A. Brent, Molecular Endocrinology Laboratory, Building 114, Room 230, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073. Phone: 310-268-3735; Fax: 310-268-4982; E-mail: gbrent{at}ucla.edu.

Key Words: sodium/iodide symporter • retinoic acid • MCF-7 • PI3K • RAR

Iodide uptake in the thyroid and breast is mediated by the sodium/iodide symporter (NIS). NIS activation is used for radioiodide imaging and therapeutic ablation of thyroid carcinoma. NIS is expressed in >70% of breast cancers but at a level insufficient for radioiodine treatment. All-trans retinoic acid (tRA) induces NIS gene expression and functional iodide uptake in human breast cancer cell lines and mouse breast cancer models. tRA usually regulates gene expression by direct interaction of RA receptor (RAR) with a target gene, but it can also act through nongenomic pathways. We report a direct influence of tRA treatment on the phosphoinositide 3-kinase (PI3K) signal transduction pathway that mediates tRA-induced NIS expression in MCF-7 breast cancer cells. MCF-7 cells express all three RAR isoforms, , β, and , and RXR. We previously identified RARβ and RXR as important for NIS induction by tRA. Treatment with LY294002, the PI3K inhibitor, or p85 knockdown with siRNA abolished tRA-induced NIS expression. Immunoprecipitation experiments and glutathione S-transferase pull-down assay showed a direct interaction between RARβ2, RXR, and p85. RA also induced rapid activation of Akt in MCF-7 cells. Treatment with an Akt inhibitor or Akt knockdown with siRNA reduced NIS expression. These findings indicate that RA induction of NIS in MCF-7 cells is mediated by rapid activation of the PI3K pathway and involves direct interaction with RAR and retinoid X receptor. Defining these mechanisms should lead to methods to further enhance NIS expression, as well as retinoid targets that influence growth and differentiation of breast cancer. [Cancer Res 2009;69(8):3443–50]