Endocrine Abstracts

The ability of thyroid cells to specifically uptake radioiodine is frequently compromised in the neoplastic setting, particularly in older patients with poorly differentiated thyroid cancer and larger metastases, resulting in a 10-year survival rate of less than 10%. The mechanisms which govern cellular iodide uptake via the sodium iodide symporter (NIS) have been elucidated with increasing molecular clarity over the past 35 years. NIS is regulated in a tissue-specific manner,...

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Most of the oncogenic events in thyroid cancer are known, and the pathways which govern thyroid cell proliferation have been exquisitely mapped. However, existing knowledge does not fully explain the genetic complexity of thyroid cancer, or reveal whether tumours are likely to be benign, malignant, or resistant to treatment. Whilst mutations and chromosomal rearrangements are central to the aetiology of DTC, the altered expression of proto-oncogenes and tumour suppressor genes...

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 abi...

Effective treatment of differentiated thyroid cancer relies on a multifaceted approach often including administration of 131I to ablate residual cancer cells post-surgery. The success of this treatment hinges upon adequate uptake of iodide by malignant thyroid follicular cells. In a subset of patients, dedifferentiation of the carcinoma can result in aberrant expression and trafficking of the iodide transport protein, the sodium iodide symporter (NIS), resulting in ...

Whilst the majority of differentiated thyroid cancers (DTC) have oncogenic mutations, a significant minority may be driven by the overexpression of proto-oncogenes. PTTG and PBF are proto-oncogenes which are induced in DTC, elicit tumours in xenograft models and interact in vitro, where PBF shuttles PTTG into the nucleus. However, the relative contributions of each gene to DTC has not been delineated. Here, we constructed a bi-transgenic murine model over-expressing b...

The sodium iodide symporter (NIS) mediates the uptake of iodide into thyroid follicular cells. The pituitary tumor transforming gene (PTTG) is a multifunctional oncogene which stimulates expression of fibroblast growth factor-2 (FGF-2) via PTTG binding factor (PBF). PTTG and FGF-2 inhibit iodide uptake in rat thyroid FRTL5 cells and PTTG and PBF repress NIS mRNA expression and iodide uptake in primary human thyroid cultures. To determine whether this regulation is a direct tra...

Dysregulation of sodium-iodide symporter (NIS) function is common in differentiated thyroid cancer, resulting in sub-optimal radioiodide therapy and poorer clinical outcome. Recent developments in identifying proteins that regulate the function of the sodium iodide symporter have highlighted two proteins involved in internalisation of NIS from the plasma membrane: AP-2 and moesin. Clathrin-mediated endocytosis (CME) of NIS is facilitated through the adaptor protein 2 (AP2) com...

Metastasis is a multistep process responsible for the vast majority of endocrine cancer deaths. We have previously identified the proto-oncogene PBF to be upregulated in differentiated thyroid cancer, and recently PBF expression has been correlated with distant thyroid cancer metastasis at diagnosis. Further, PBF potently induces breast cancer cell invasion in vitro, and our recent in vivo data demonstrate that colorectal tumours with higher PBF protein expre...

PTTG is a multifunctional proto-oncogene overexpressed in thyroid cancers, which binds to p53 and modulates its function. PBF, a binding partner of PTTG, is also overexpressed in thyroid cancer and can transform cells independently of PTTG. Moreover, subcutaneous expression of PBF elicits large tumours in nude mice. Given the established role of ionising radiation in thyroid tumourigenesis, we investigated the relationship between PBF and the tumour suppressor protein p53. PBF...