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• Title: Sodium/Iodide Symporter Regulation by Oncogenes in the Mammary Gland and Thyroid Gland Using Mouse Models
• Author : Katherine A.B. Knostman
• Release Date : January 19, 2013
• Genre: Medical,Books,Professional & Technical,Science & Nature,
• Pages : * pages
• Size : 14392 KB

Description

The objectives of this study are (1) to develop targeted sodium/iodide symporter (NIS)-mediated radionuclide imaging and therapy of breast cancer by elucidating NIS regulatory mechanisms; and (2) to establish an inducible animal model enabling non-invasive monitoring of thyroid RET/PTC1 oncogene expression and tumorigenesis.NIS-mediated iodide uptake in thyroid cells is the basis of radioiodine imaging and post-surgical ablation of thyroid tumors. The majority of human breastcancers express NIS, yet few have iodide uptake activity. PI3K and cAMP were identified as important signaling molecules in breast cancer NIS upregulation using mouse models. In MCF-7 human breastcancer cells, activation of PI3K p110 alpha led to unglycosylated NIS protein lacking cell surface trafficking required for iodide uptake ability. Intracellular NIS expression was correlated with PI3K upregulation in an array of human breast tumors. Thus, the PI3K pathway likely plays a role in the paradox between NIS expression and iodide uptake in breast cancer patients.Ret/PTC1 oncogene is caused by radiation exposure and has been shown to cause thyroid tumors in transgenic mice. We created a doxycycline-inducible mouse model of thyroid RET/PTC1 and luciferase co-expression to allow for study of acute effect of RET/PTC1 oncogene on thyroid pathophysiology as well as noninvasive bioluminescent imaging of transgene expression. By crossbreeding transgenic mice carrying thyroid-targeted rtTA gene with tetracycline responder mice carrying the RET/PTC1 and firefly luciferase genes, we developed a mouse with doxycycline-regulated, functional thyroid RET/PTC1 expression. However, the level of RET/PTC1 expression in this mouse model was not sufficient to result in thyroid lesions after 3.5 months of doxycycline treatment, nor were lesions present in any of the doxycycline-independent bitransgenic lines up to age 10.5 months. This study indicates that modest RET/PTC1 expression might not destine a thyroid gland to tumorigenesis and could account for the long tumor latency in humans post-radiation exposure.

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