title: Significance of nuclear p-Akt in endometrial carcinogenesis: rapid translocation of p-Akt into the nucleus by estrogen, possibly resulting in inhibition of apoptosis.
abstract: BACKGROUND
  Endometrial endometrioid adenocarcinoma (endometrial cancer) develops through endometrial hyperplasia caused by estrogenic hyperstimulation. Estrogen is known to activate growth factor signaling pathways, resulting in cellular proliferation, but precisely how has not been clarified. The aim of this study was to investigate the significance of estrogen and downstream factors such as the MAPK (MEK, ERK) and Akt pathways in endometrial carcinogenesis.
  
  
  METHODS
  The expression of p-MEK, p-ERK, and p-Akt was analyzed immunohistochemically in normal, hyperplastic, and neoplastic endometria. The estrogenic effect on p-Akt was examined using an endometrial cancer cell line (Ishikawa cells). The estrogenic effect on the apoptosis of Ishikawa cells was assessed by the TUNEL method.
  
  
  RESULTS
  Phospho-MEK (p-MEK) and p-ERK expression levels were similar among histological types but correlated with each other. The nuclear p-Akt labeling index (LI) was higher in cancer than in normal endometrium and hyperplasia. The nuclear p-Akt LI of well-differentiated cancer (G1) was higher than that of moderately (G2) or poorly (G3) differentiated cancers. The nuclear expression of p-Akt was correlated with that of estrogen receptor α (ER-α). The nuclear p-Akt level was significantly correlated with prognosis in cases of G1. In Ishikawa cells transfected with ERα, p-Akt was translocated into the nucleus from the cytoplasm in 1 to 3 hours after estrogenic stimulation. Further, apoptosis induced by H2O2 was inhibited by estrogen in the ER-α-positive cells.
  
  
  CONCLUSIONS
  The translocation of p-Akt into the nucleus by estrogen may be related to the suppression of apoptosis by estrogen and consequently to endometrial carcinogenesis and prognosis in G1 endometrial cancer.
authors.affiliation: Department of Cellular and Histopathology, Kitasato University, Sagamihara, Kanagawa, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Abe
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
authors.forename: Shinpei
authors.initials: S
authors.lastname: Tsunoda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuramoto
authors.forename: Isao
authors.initials: I
authors.lastname: Okayasu
mesh_terms: D017209:Apoptosis; D018269:Carcinoma, Endometrioid / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004967:Estrogens; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases