title: Chemopreventive effects of metformin on obesity-associated endometrial proliferation.
abstract: OBJECTIVE
  Obesity is a significant contributing factor to endometrial cancer risk. We previously demonstrated that estrogen-induced endometrial proliferation is enhanced in the context of hyperinsulinemia and insulin resistance. In this study, we investigate whether pharmacologic agents that modulate insulin sensitivity or normalize insulin levels will diminish the proliferative response to estrogen.
  
  
  METHODS
  Zucker fa/fa obese rats and lean controls were used as models of hyperinsulinemia and insulin resistance. Insulin levels were depleted in ovariectomized rats following treatment with streptozotocin, or modulated by metformin treatment. The number of BrdU-incorporated cells, estrogen-dependent proliferative and antiproliferative gene expression, and activation of mTOR and ERK1/2 MAPK signaling were studied. A rat normal endometrial cell line RENE1 was used to evaluate the direct effects of metformin on endometrial cell proliferation and gene expression in vitro.
  
  
  RESULTS
  Streptozotocin lowered circulating insulin levels in obese rats and decreased the number of BrdU-labeled endometrial cells even in the presence of exogenous estrogen. Treatment with the insulin-sensitizing drug metformin attenuated estrogen-dependent proliferative expression of c-myc and c-fos in the obese rat endometrium compared to untreated controls and was accompanied by inhibition of phosphorylation of the insulin and IGF1 receptors (IRβ/IGF1R) and ERK1/2. In vitro studies indicated metformin inhibited RENE1 proliferation in a dose-dependent manner.
  
  
  CONCLUSIONS
  These findings suggest that drugs that modulate insulin sensitivity, such as metformin, hinder estrogen-mediated endometrial proliferation. Therefore, these drugs may be clinically useful for the prevention of endometrial cancer in obese women.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Celestino
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schmandt
authors.forename: Adrienne S
authors.initials: AS
authors.lastname: McCampbell
authors.forename: Diana L
authors.initials: DL
authors.lastname: Urbauer
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Meyer
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Burzawa
authors.forename: Marilyn
authors.initials: M
authors.lastname: Huang
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Yates
authors.forename: David
authors.initials: D
authors.lastname: Iglesias
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006946:Hyperinsulinism / Q000188:drug therapy* / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D009765:Obesity / Q000150:complications*; D011519:Proto-Oncogenes / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D004958:Estradiol; D013311:Streptozocin; D008687:Metformin
keywords: estrogen; insulin resistance; obesity