title: Involvement of Akt, Ras and cell cycle regulators in the potential development of endometrial hyperplasia in women with polycystic ovarian syndrome.
abstract: OBJECTIVE
  To examine whether the abundance, localization, and/or activity of cell cycle regulators CDK2, Cyclin E, p27, and survival proteins AKT and Ras in PCOS-associated endometria (with and without hyperplasia) differ from non-PCOS endometria.
  
  
  METHODS
  The expression of CDK2, Cyclin E, p27, AKT and Ras was measured by immunohistochemistry and/or Western blot in 9 normal endometria (NE), 12 endometria from PCOS patients without endometrial hyperplasia (PCOSE), 7 endometria from PCOS women with endometrial hyperplasia (HPCOSE), and 9 endometria from patients with endometrial hyperplasia (HE). The activity of CDK2 was assessed by an in vitro kinase assay.
  
  
  RESULTS
  CDK2, Cyclin E and p27 proteins were expressed mainly in the endometrial epithelial cells of the studied groups. No change in the activity of CDK2 was observed in total extracts obtained from the tissue samples. However, the nuclear expression of CDK2 in epithelial cells was slightly elevated in PCOSE and significantly increased in HPCOSE when compared to NE. Higher expression of p27 was detected in the cytoplasm of epithelial cells of PCOSE and HPCOSE when compared to NE. Also, we found an increment in Ser473-AKT phosphorylation and an over-expression of the Ras oncogene in endometria of patients with PCOS.
  
  
  CONCLUSIONS
  The PCOS condition is associated with increased Ser473-AKT phosphorylation, elevated expression of Ras, increased cytoplasmic abundance of p27, and increased nuclear abundance of CDK2 in the endometrial epithelial cells. These biological events could potentially provide a chance for endometrial cells from PCOS patients to exit the controlled cell cycle and become hyperplastic at a later stage.
authors.affiliation: Institute of Nutrition and Food Technology, University of Chile, Chile.
authors.forename: A
authors.initials: A
authors.lastname: Villavicencio
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, USA.
authors.forename: A
authors.initials: A
authors.lastname: Goyeneche
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, USA.
authors.forename: C
authors.initials: C
authors.lastname: Telleria
authors.affiliation: Department of Cell Biology and Anatomy, Miller School of Medicine, University of Miami, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bacallao
authors.affiliation: Department of Pathology, San Borja-Arriarán Clinical Hospital, School of Medicine, University of Chile, Chile.
authors.forename: F
authors.initials: F
authors.lastname: Gabler
authors.affiliation: Institute of Maternal and Child Research, School of Medicine, University of Chile, Chile.
authors.forename: A
authors.initials: A
authors.lastname: Fuentes
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, University of Chile Clinical Hospital, Chile. Electronic address: mvega@med.uchile.cl.
authors.forename: M
authors.initials: M
authors.lastname: Vega
mesh_terms: D000328:Adult; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004714:Endometrial Hyperplasia / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010766:Phosphorylation; D011085:Polycystic Ovary Syndrome / Q000201:enzymology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000378:metabolism; D018631:ras Proteins / Q000096:biosynthesis*
chemical_list: C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018631:ras Proteins