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AKT Activation Promotes Metastasis in a Mouse Model of Follicular Thyroid Carcinoma

Laboratory of Molecular Biology (C.S.K., Y.K., S.-Y.C.) and Experimental Immunology Branch (M.K.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; and Divisions of Endocrinology and Oncology, Ohio State University School of Medicine, and Arthur G. James Cancer Center (V.V.V., M.S., M.D.R.), Columbus, Ohio 43210

Address all correspondence and requests for reprints to: Dr. Sheue-yann Cheng, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264. E-mail: sycheng{at}helix.nih.gov.

The phosphatidylinositol 3-kinase/AKT pathway is crucial to many cell functions, and its dysregulation in tumors is a common finding. The molecular basis of follicular thyroid cancer metastasis is not well understood but may also be influenced by AKT activation. We previously created a knockin mutant mouse that expresses a mutant thyroid hormone receptor-ß gene (TRßPV mouse) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. In this study, we investigated whether our mouse model exhibits similar AKT activation as human follicular thyroid cancer. Western blot analysis on thyroids from both wild-type and TRß^PV/PV mice revealed elevation of activated AKT in TRß^PV/PV mice. Immunohistochemistry and confocal microscopy reveal activated AKT in both the thyroid and metastatic lesions of TRß^PV/PV mice. Whereas all three AKT isoforms were overexpressed in primary tumors from TRß^PV/PV mice in the cytoplasm of thyroid cancer cells, only AKT1 was also found in the nucleus, matching the localization of activated AKT in a pattern similar to human follicular thyroid cancer. In the metastases, all AKT isoforms correlated with phosphorylated AKT nuclear localization. We created primary thyroid cell lines derived from TRß^PV/PV mice and found reduction of phosphorylated AKT levels or AKT downstream targets diminishes cell motility. Activated AKT is common to both human and mouse follicular thyroid cancer and is correlated with increased cell motility in vitro and metastasis in vivo. Thus, TRß^PV/PV mice could be used to further dissect the detailed pathways underlying the progression and metastasis of follicular thyroid carcinoma.

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