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Open Access Highly Accessed Research article

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

Katherine AB Knostman1, James A McCubrey2, Carl D Morrison3, Zhaoxia Zhang4, Charles C Capen1 and Sissy M Jhiang5*

Author Affiliations

1 Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA

2 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, USA

3 Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA

4 Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio 43210, USA

5 Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio 43210, USA

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BMC Cancer 2007, 7:137  doi:10.1186/1471-2407-7-137

Published: 25 July 2007

Abstract

Background

The sodium/iodide symporter (NIS) is a membrane glycoprotein mediating active iodide uptake in the thyroid gland and is the molecular basis for radioiodide imaging and therapeutic ablation of thyroid carcinomas. NIS is expressed in the lactating mammary gland and in many human breast tumors, raising interest in similar use for diagnosis and treatment. However, few human breast tumors have clinically evident iodide uptake ability. We previously identified PI3K signaling as important in NIS upregulation in transgenic mouse models of breast cancer, and the PI3K pathway is commonly activated in human breast cancer.

Methods

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).

Results

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.

Conclusion

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.