title: Lean Body Weight and Metformin Are Insufficient to Prevent Endometrial Hyperplasia in Mice Harboring Inactivating Mutations in PTEN.
abstract: OBJECTIVE
  Obesity is a major risk factor for endometrial cancer. We evaluated whether obesity exacerbates progression of endometrial hyperplasia (EH) using the PRCre/+ PTENflox/+ mouse model and examined if the type 2 diabetes drug, metformin, could prevent EH.
  
  
  METHODS
  Twenty obese (PRCre/+ PTENflox/+) mice were maintained on a high-fat diet, while 20 lean mice ate a matching low-fat diet. Ten mice from each group received metformin (1,000 mg/day) in drinking water. Mice were euthanized at 26 weeks. Uterine tissue was scored for degree of EH. Immunohistochemical staining for Ki67 was used to evaluate cellular proliferation. Markers of PI3K/AKT/mTOR activity were evaluated by immunohistochemistry using activation-specific antibodies. Serum adiponectin was quantified by ELISA.
  
  
  RESULTS
  Obesity had no effect on the extent of EH in (PRCre/+ PTENflox/+) mice. While metformin significantly altered circulating adiponectin levels in obese and lean animals, it had no effect on EH. There were no differences in endometrial proliferation as measured by Ki67 staining. Neither obesity nor metformin altered PI3K/AKT/mTOR activity in these animals.
  
  
  CONCLUSIONS
  Weight and metformin did not affect the severity of EH resulting from PTEN inactivation. Alternative mouse models of early endometrial cancer are required for preclinical cancer prevention studies.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Iglesias
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Celestino
authors.forename: Charlotte C
authors.initials: CC
authors.lastname: Sun
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Yates
authors.forename: Rosemarie E
authors.initials: RE
authors.lastname: Schmandt
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D004714:Endometrial Hyperplasia / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*
chemical_list: D052242:Adiponectin; D007004:Hypoglycemic Agents; D008687:Metformin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse