| First Author | Dobson ME | Year | 2011 |
| Journal | Endocrinology | Volume | 152 |
| Issue | 11 | Pages | 4455-65 |
| PubMed ID | 21952241 | Mgi Jnum | J:177181 |
| Mgi Id | MGI:5294342 | Doi | 10.1210/en.2011-1178 |
| Citation | Dobson ME, et al. (2011) Pioglitazone Induces a Proadipogenic Antitumor Response in Mice with PAX8-PPAR{gamma} Fusion Protein Thyroid Carcinoma. Endocrinology 152(11):4455-65 |
| abstractText | Approximately 35% of follicular thyroid carcinomas harbor a chromosomal translocation that results in expression of a paired box gene 8-peroxisome proliferator-activated receptor gamma gene (PPARgamma) fusion protein (PPFP). To better understand the oncogenic role of PPFP and its relationship to endogenous PPARgamma, we generated a transgenic mouse model that combines Cre-dependent PPFP expression (PPFP;Cre) with homozygous deletion of floxed Pten (PtenFF;Cre), both thyroid specific. Although neither PPFP;Cre nor PtenFF;Cre mice develop thyroid tumors, the combined PPFP;PtenFF;Cre mice develop metastatic thyroid cancer, consistent with patient data that PPFP is occasionally found in benign thyroid adenomas and that PPFP carcinomas have increased phosphorylated AKT/protein kinase B. We then tested the effects of the PPARgamma agonist pioglitazone in our mouse model. Pioglitazone had no effect on PtenFF;Cre mouse thyroids. However, the thyroids in pioglitazone-fed PPFP;PtenFF;Cre mice decreased 7-fold in size, and metastatic disease was prevented. Remarkably, pioglitazone caused an adipogenic response in the PPFP;PtenFF;Cre thyroids characterized by lipid accumulation and the induction of a broad array of adipocyte PPARgamma target genes. These data indicate that, in the presence of pioglitazone, PPFP has PPARgamma-like activity that results in trans-differentiation of thyroid carcinoma cells into adipocyte-like cells. Furthermore, the data predict that pioglitazone will be therapeutic in patients with PPFP-positive carcinomas. |
