Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment

Martin L. Read, Greg D. Lewy, Jim C.W. Fong, Neil Sharma, Robert I. Seed, Vicki E. Smith, Erica Gentilin, Adrian Warfield, Margaret C. Eggo, Jeffrey A. Knauf, Wendy E. Leadbeater, John C. Watkinson, Jayne A. Franklyn, Kristien Boelaert, Christopher J. McCabe*

*Corresponding author for this work

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Abstract

Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized protooncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.

Original languageEnglish
Pages (from-to)6153-6164
Number of pages12
JournalCancer Research
Volume71
Issue number19
DOIs
Publication statusPublished - 1 Oct 2011

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©2011 American Association for Cancer Research

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Read, M. L., Lewy, G. D., Fong, J. C. W., Sharma, N., Seed, R. I., Smith, V. E., Gentilin, E., Warfield, A., Eggo, M. C., Knauf, J. A., Leadbeater, W. E., Watkinson, J. C., Franklyn, J. A., Boelaert, K., & McCabe, C. J. (2011). Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment. Cancer Research, 71(19), 6153-6164. https://doi.org/10.1158/0008-5472.CAN-11-0720