title: Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma.
abstract: Approximately 35% of follicular thyroid carcinomas harbor a chromosomal translocation that results in expression of a paired box gene 8-peroxisome proliferator-activated receptor γ gene (PPARγ) fusion protein (PPFP). To better understand the oncogenic role of PPFP and its relationship to endogenous PPARγ, 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 PPARγ 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 PPARγ target genes. These data indicate that, in the presence of pioglitazone, PPFP has PPARγ-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.
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Unit for Laboratory Animal Medicine, Department of Pathology, University of Michigan Medical School, 1150 West Medical Center Drive, 5560 MSRB2, Ann Arbor, Michigan 48109, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Dobson
authors.forename: Ericka
authors.initials: E
authors.lastname: Diallo-Krou
authors.forename: Vladimir
authors.initials: V
authors.lastname: Grachtchouk
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Yu
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Colby
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Koenig
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D047495:PPAR gamma / Q000235:genetics*; D051761:Paired Box Transcription Factors / Q000235:genetics*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014178:Translocation, Genetic
chemical_list: D015514:Oncogene Proteins, Fusion; D000072636:PAX8 Transcription Factor; D047495:PPAR gamma; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D045162:Thiazolidinediones; D000077205:Pioglitazone