Characterisation of thyroid structure and function in the PBF knockout mouse

Dr Vicki Smith, MRC Research Fellow

School of Clinical and Experimental Medicine, University of Birmingham

We are interested in the study of a protein known as PBF that is upregulated in thyroid cancer. In mice, high levels of PBF result in greatly enlarged thyroid glands. PBF also prevents two proteins that are important for thyroid hormone production from functioning properly. One of these proteins is crucial for the treatment of thyroid cancer with radioiodine.

We believe that PBF is an important regulator of the thyroid and to understand more about how it does this, we propose to study a mouse, which does not have the PBF protein. We will analyse the effect of not having PBF on the size of the thyroid, on how the thyroid functions and how thyroid disease is affected. A better understanding of this will be especially important in finding ways to prevent PBF from reducing radioiodine uptake. This should improve therapy and outcome of thyroid cancer, particularly for the subset of patients who are currently very difficult to treat with radioiodine, and who have less than a 50% chance of surviving 5 years.

Interim Report

Thyroid cancers and multinodular goitres often contain high levels of a protein called PBF. Those thyroid cancers with high PBF expression are more likely to recur and are associated with a reduced survival rate. We have previously shown that increasing the amount of PBF in mice results in significantly enlarged thyroid glands and under certain conditions can drive tumour formation. However, the way in which this occurs is still not fully understood.

We have also shown that PBF can impair the function of two proteins that are important for thyroid hormone production. One of these proteins, NIS, is responsible for taking up iodide from the blood into the thyroid and is therefore crucial both for thyroid hormone synthesis and for the treatment of thyroid cancer with radioiodine. The other protein, MCT8, is important for secreting thyroid hormone from the thyroid into the blood.

These studies highlight PBF as a protein involved in the regulation of thyroid hormone biosynthesis and secretion that, when upregulated, can disrupt thyroid cell growth, contributing to goitre and cancer. Further, the effectiveness of critical thyroid cancer treatment is reduced.

This indicates that PBF is an important regulator of the thyroid and to understand more about how it does this, the aim of this study is to characterise a mouse which does not have the PBF protein, a PBF knock-out mouse. Our main objectives are to analyse the effect of not having PBF on the size of the thyroid, on how the thyroid functions and how thyroid disease is affected.

The creation of mouse models is a complex process and, after initial successes, we have identified possible issues with the fertility of our mouse line, suggesting that PBF is also important for successful reproduction. This is a potentially very interesting observation and will be investigated further while we overcome these issues. In the meantime we are currently carrying out parallel experiments using thyroid cell lines in which we can potently reduce the amount of PBF expression to provide important insights that will direct our studies in the coming months.

Overall, these studies seek to further increase our understanding of the precise role of PBF in the regulation of thyroid growth, function and disease. They will be especially important in finding ways to prevent PBF from reducing radioiodine uptake, and therefore improve treatment of thyroid tumours and their metastases. This should improve therapy and outcome of thyroid cancer, particularly for the subset of patients who are currently very difficult to treat with radioiodine, and who have a less than 50% chance of surviving 5 years.