title: Cumulative alterations of p27-related cell-cycle regulators in the development of endometriosis-associated ovarian clear cell adenocarcinoma.
abstract: OBJECTIVE
  To identify the key cell-cycle dysregulations in the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA).
  
  
  RESULTS
  Expression of p27(Kip1)-interacting cell-cycle regulators, such as p27(Kip1) itself, Skp2, cyclin-dependent kinase subunit 1 (Cks1), cyclin A and cyclin E, and Ki67 labelling index (LI), were analysed by immunohistochemistry in 23 CCAs with 36 endometriotic or atypical endometriotic lesions adjacent to CCA from a cohort of 23 patients, and in 31 cases of solitary endometriosis. The cell-cycle regulators examined were overexpressed (Skp2, Cks1, cyclin A and cyclin E; P < 0.01, each) or down-regulated (p27(Kip1), P = 0.044) significantly more frequently in the CCAs than in the adjacent endometriosis. The frequency of Skp2 overexpression was significantly higher in atypical endometriosis than in endometriosis, and the frequency of Skp2 and cyclin A overexpression was significantly higher in CCA than in atypical endometriosis (P < 0.01, each). Mean Ki67 LI increased from endometriosis (8.4%) through atypical endometriosis (21.4%) to CCA (46.9%), with statistical significance between each component (P < 0.01, each). The frequency of cell-cycle regulator expression and mean Ki67 LIs were not significantly different between solitary endometriosis and endometriosis adjacent to CCA.
  
  
  CONCLUSIONS
  Alteration of the p27(Kip1)-interacting cell-cycle regulators appeared strongly involved in the progression of endometriosis-associated ovarian clear cell carcinogenesis through increasing cell proliferative activity.
authors.affiliation: Department of Basic Pathology, National Defence Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
authors.forename: Kosuke
authors.initials: K
authors.lastname: Miyai
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.forename: Seiichi
authors.initials: S
authors.lastname: Tamai
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsubara
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D015536:Down-Regulation; D004715:Endometriosis / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism
chemical_list: C436291:CDKN1B protein, human; C093090:CKS1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019925:Cyclin A; D047908:Intracellular Signaling Peptides and Proteins; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; D018844:Cyclin-Dependent Kinases