Activation of the PI3 kinase pathway by retinoic acid mediates sodium/iodide symporter induction and Iodide transport in MCF-7 breast cancer cells

Abstract

Iodide uptake in the thyroid and breast is mediated by the sodium/iodide symporter (MS). MS activation is used for radioiodide imaging and therapeutic ablation of thyroid carcinoma. MS is expressed in >70% of breast cancers but at a level insufficient for radioiodine treatment. All-fr«ras retinoic acid (tRA) induces MS 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 MS expression in MCF-7 breast cancer cells. MCF-7 cells express all three RAR isoforms, α, β, and γ, and RXRα. We previously identified RARβ and RXRα as important for MS induction by tRA. Treatment with LY294002, the PI3K inhibitor, or p85α knockdown with siRNA abolished tRA- induced MS expression. Immunoprecipitation experiments and glutathione S-transferase pull-down assay showed a direct interaction between RARβ2, RXRα, and p85α. RA also induced rapid activation of Akt in MCF-7 cells. Treatment with an Akt inhibitor or Akt knockdown with siRNA reduced MS expression. These findings indicate that RA induction of MS 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 MS expression, as well as retinoid targets that influence growth and differentiation of breast cancer. © 2009 American Association tor Cancer Research.