TY - JOUR T1 - Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the <em>PTEN</em> heterozygote murine model JF - International Journal of Gynecologic Cancer JO - Int J Gynecol Cancer SP - 329 LP - 338 DO - 10.1111/j.1525-1438.2007.01002.x VL - 18 IS - 2 AU - W. Wu AU - J. Celestino AU - M. R. Milam AU - K. M. Schmeler AU - R. R. Broaddus AU - L. H. Ellenson AU - K. H. Lu Y1 - 2008/02/01 UR - http://ijgc.bmj.com/content/18/2/329.abstract N2 - 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&lt; 0.02 and P&lt; 0.03, respectively). Rosiglitazone also induced apoptosis in both Hec-1-A (P&lt; .001) and Ishikawa (P&lt; .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&lt; 0.0001) and increased apoptosis of glandular endometrial epithelial cells (B vs C; 2.8% vs 22.4%; P&lt; 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. ER -