Manipulating PBF/PTTG1IP phosphorylation status to improve radioiodine uptake in thyroid and other tumours

The clinical effectiveness of ablative radioiodine treatment is limited by the ability of the sodium iodide symporter (NIS) to uptake 131I. A significant proportion of well-differentiated thyroid tumours are unable to concentrate sufficient radioiodine for effective therapy, and in other tumour models such as breast, where radioiodine uptake would be an attractive therapeutic option, uptake is insufficient. Pituitary tumor-transforming gene-binding factor (PBF/ PTTG1IP) is over-expressed in multiple cancers including thyroid and breast, and potently represses NIS function in thyroid cancer. We now demonstrate that the post-translational mechanism by which PBF represses NIS is applicable to non-thyroid tumour cells including breast and prostate. Crucially, we describe a method by which PBF repression of NIS may be overcome in human tumours. We identify PBF as a tyrosine phospho-protein which specifically binds the proto-oncogene tyrosine-protein kinase Src in mass spectrometry, GST-pulldown and co-immunoprecipitation assays. Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in plasma membrane retention and an inability to bind NIS. The Src inhibitor PP1 inhibits PBF phosphorylation in multiple cell lines in vitro, including human primary thyroid cells. Of direct clinical importance, PP1 overcomes PBF repression of iodide uptake in human primary thyroid cells. Thus, we propose that targeting PBF phosphorylation at residue Y174 via tyrosine kinase inhibitors may be a novel therapeutic strategy to enhance the efficacy of ablative radioiodine treatment in thyroid and other endocrine and endocrine-related tumours.