PI3K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer

NIS expression, subcellular localization, and function were analyzed in MCF-7 human breast cancer cells and MCF-7 cells stably or transiently expressing PI3K p110alpha subunit using Western blot of whole cell lysate, cell surface biotinylation Western blot and immunofluorescence, and radioiodide uptake assay, respectively. NIS localization was determined in a human breast cancer tissue microarray using immunohistochemical staining (IHC) and was correlated with pre-existing pAkt IHC data. Statistical analysis consisted of Student's t-test (in vitro studies) or Fisher's Exact Test (in vivo correlational studies).In this study, we demonstrate that PI3K activation in MCF-7 human mammary carcinoma cells leads to expression of underglycosylated NIS lacking cell surface trafficking necessary for iodide uptake ability. PI3K activation also appears to interfere with cell surface trafficking of exogenous NIS as well as all-trans retinoic acid-induced endogenous NIS. A correlation between NIS expression and upregulation of PI3K signaling was found in a human breast cancer tissue microarray.Thus, the PI3K pathway likely plays a major role in the discordance between NIS expression and iodide uptake in breast cancer patients. Further study is warranted to realize the application of NIS-mediated radioiodide ablation in breast cancer.Breast cancer is one of the most common cancers in women in North America, where incidence is highest in the world [1]. In the United States, more than 200,000 newly diagnosed cases were estimated in the year 2005. While treatment with surgery, chemotherapy, hormonal and radiation therapy, and antibodies targeting the Her-2/neu growth promoting protein have slowed disease progression or resulted in remission in many patients, metastatic disease still causes death in the majority of affected patients within 5 years of diagnosis. Thus, continued discovery of novel methods of detecting and treating residual and metastatic breast cancer are of extremely hi