Endocrine Abstracts

Thyroid malignancies are the most common type of endocrine tumors. Of the various histological sub-types, anaplastic thyroid carcinoma (ATC) represents 2% of all cases but is responsible for most of the thyroid cancer related death.

Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of human cancer. Moreover, to date, there is a paucity of relevant models to study how the signature genetic abnormalities detected in ATC contribute to the pathogenesis of this disease.

Mutational activation of the BRAF proto-oncogene is detected in ~40% of papillary thyroid cancers (PTC) and also in a significant percentage of ATC.

Moreover, BRAF mutation is frequently found in combination with gain-of-function mutations in PIK3CA (encoding the p110 catalytic subunit of PI3’-kinase-a) or loss-of-function alterations in either TP53 or PTEN. Using mice with conditional, thyrocyte-specific expression of BRAFV600E, we have previously described a model of PTC¹. However, as in humans, BRAFV600E-induced PTC in mice is indolent and rarely leads to lethal disease.

Using mice carrying a conditional allele of Pik3ca (lat-1047R²) we demonstrate that expression of mutationally activated PIK3CAH1047R is largely without effect in thyrocytes. However, when BRAFV600E expressed is combined with PIK3CAH1047R in thyrocytes, mice develop ATC that results in rapid lethality.

These data indicate that BRAFV600E cooperates with PIK3CAH1074R to promote progression of ATC in the mouse. This genetically relevant mouse model of ATC will be an invaluable platform for testing pathway-targeted therapies for the prevention and treatment of thyroid cancer in the preclinical context.

References: 1. Charles et al. Cancer Res 2011 71 3863–3871.

2. Kinross et al. J Clin Invest 2012 122 553–557.