Approximately 35% of
follicular thyroid carcinomas and a small fraction of
follicular adenomas are associated with a t(2;3)(q13;p25)
chromosomal translocation that fuses paired box gene 8 (PAX8) with the
peroxisome proliferator-activated receptor-gamma gene (PPARG), resulting in expression of a PAX8-PPARgamma fusion
protein, PPFP. The mechanism by which PPFP contributes to follicular thyroid
neoplasia is poorly understood. Therefore, we have created mice with thyroid-specific expression of PPFP. At 1 yr of age, 25% of PPFP mice demonstrate mild thyroid
hyperplasia. We bred these mice to mice with thyroid-specific single-allele deletion of the
tumor suppressor Pten, denoted ThyPten(+/-). In humans, PTEN deletion is associated with
follicular adenomas and
carcinomas, and in mice, deletion of one Pten allele causes mild thyroid
hyperplasia. We found that PPFP synergizes with ThyPten(+/-) to cause marked thyroid
hyperplasia, but
carcinomas were not observed. AKT phosphorylation was increased as expected in the ThyPten(+/-) thyroids, and also was increased in the PPFP thyroids and in human PPFP follicular
cancers. Staining for the cell cycle marker Ki-67 was increased in the PPFP, ThyPten(+/-), and PPFP;ThyPten(+/-) thyroids compared with wild-type thyroids. Several genes with increased expression in PPFP
cancers also were found to be increased in the thyroids of PPFP mice. This transgenic mouse model of thyroidal PPFP expression exhibits properties similar to those of PPFP
thyroid cancers. However, the mice develop thyroid
hyperplasia, not
carcinoma, suggesting that additional events are required to cause
follicular thyroid cancer.