Endocrine Abstracts

The treatment of thyroid cancer has not changed substantially for several decades, in contrast to most other tumour types. Total thyroidectomy and administration of ablative radioiodine remain the cornerstones of the therapeutic regimen, which is associated with a good 5-year survival rate. Nonetheless, thyroid cancer treatment is not perfect, and several hurdles remain to be overcome. Radioiodine ablation of differentiated thyroid cancers and their metastases utilises the ability of the thyroid to accumulate iodide. Treatment is therefore dependent on the expression and function of the sodium iodide symporter (NIS), which transports iodide into thyroid follicular cells for thyroid hormone biosynthesis. However, in thyroid cancers, NIS expression levels are variable and the avidity of the thyroid for radioiodine can be reduced by transcriptional and post-translational effects on NIS expression. Whilst the mechanisms which diminish NIS activity in thyroid cancer are not fully understood, we have recently elucidated two discrete routes by which PTTG binding factor (PBF) represses iodide uptake through the down-regulation of NIS function. PBF is a protein described so far in fewer than 10 publications, but which exhibits a growing multifunctionality in endocrine tumourigenesis. In the thyroid, PBF is over-expressed in tumours compared to normals, and expression correlates with early tumour recurrence. In both primary human thyroid cultures and rat thyroid FRTL-5 cells, PBF significantly represses activity of the human NIS promoter and inhibits iodide uptake. More recently, we demonstrated that PBF binds NIS in vitro in GST pull-down and co-immunoprecipitation experiments. Transient PBF over-expression is associated with a significant reduction in plasma membrane-associated NIS, and a concurrent repression of iodide uptake. Further, targeted transgenic over-expression of PBF in mouse thyroids results in reduced NIS mRNA and protein expression, and profound goitre formation. Thus PBF represents a gene which exhibits both transcriptional and post-translational repression of NIS expression and function. Given that effective radioiodine uptake remains critical to the management of differentiated thyroid cancer and its metastases, PBF represents a novel therapeutic target, particularly in the treatment of radioiodine-resistant tumours.