Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model. Issue 2 (1st February 2008)

• Record Type: Journal Article
• Authors: Wu, W.; Celestino, J.; Milam, M. R.; Schmeler, K. M.; Broaddus, R. R.; Ellenson, L. H.; Lu, K. H.
• Is Part Of: International journal of gynecological cancer. Volume 18:Issue 2(2008)
• Page Start: 329
• Page End: 338
• Publication Date: 2008-02-01
• Subjects: animal model -- endometrial hyperplasia -- PTEN -- rosiglitazone; Generative organs, Female -- Cancer -- Periodicals; 616.99465
• DOI: 10.1111/j.1525-1438.2007.01002.x
• Languages: English
• ISSNs: 1048-891X

Abstract

Abstract : PTEN mutations have been implicated in the development of endometrial hyperplasia and subsequent cancer. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists have demonstrated antineoplastic and chemopreventive effects. The purpose of this study was to evaluate the effects of the PPAR-γ agonist rosiglitazone on both PTEN wild type and PTEN null cell lines and in the PTEN heterozygote (+/−) murine model. Hec-1-A ( PTEN wild type) and Ishikawa ( PTEN null) cells were treated with rosiglitazone. Thirty-five female PTEN +/− mice were genotyped and placed into one of four groups for treatment for 18 weeks: A) PTEN wild type with 4 mg/kg rosiglitazone, B) PTEN +/− mice with vehicle, C) PTEN +/− mice with 4 mg/kg rosiglitazone, and D) PTEN +/− mice with 8 mg/kg rosiglitazone. Proliferation and apoptosis were measured by bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragmentation sites assay. Rosiglitazone caused cell growth inhibition in both Hec-1-A and Ishikawa in a dose-dependent manner ( P < 0.02 and P < 0.03, respectively). Rosiglitazone also induced apoptosis in both Hec-1-A ( P < .001) and Ishikawa ( P < .001) cells in a dose-dependent manner. In the murine model, rosiglitazone decreased proliferation of the endometrial hyperplastic lesions (B vs C; 39.7% vs 9.3% and B vs D; 39.7% vs 4.2%; P < 0.0001) and increased apoptosis of glandular endometrial epithelial cells (B vs C; 2.8% vs 22.4%; P < 0.0001 and B vs D; 2.8% vs 30.2%; P = 0.003). PPAR-γ agonist rosiglitazone inhibits proliferation and induces apoptosis in both PTEN intact and PTEN null cancer cell lines and in hyperplastic endometrial lesions in the PTEN +/ − murine model.