title: The PAC-1 dual specificity phosphatase predicts poor outcome in serous ovarian carcinoma.
abstract: OBJECTIVE
  Data regarding signal transduction pathways in human tumors are largely confined to cell line studies to date. We have recently reported on the activation and prognostic role of mitogen-activated protein kinases (MAPK) in ovarian carcinoma in effusions. The objective of the present study was to investigate the expression and clinical role of dual-specificity phosphatases (DUSP), inhibitors of MAPK signaling, in ovarian cancer cells at this site.
  
  
  METHODS
  Thirty-nine fresh frozen malignant effusions from patients diagnosed with serous ovarian carcinoma were studied for mRNA expression of the DUSP MKP-1, MKP-4, MKP-5, and PAC-1 using RT-PCR. DUSP expression was analyzed for possible correlation with patient age, disease stage, tumor grade, histological grade, chemotherapy status, and survival.
  
  
  RESULTS
  MKP-1 and PAC-1 mRNA were found in 36 and 37 effusions, respectively, with expression levels showing considerable variation. MKP-4 and MKP-5 were uniformly absent. MKP-1 showed no association with clinicopathologic parameters. However, PAC-1 expression was significantly higher in effusions obtained before the institution of treatment with both platinum compounds (P = 0.029) and paclitaxel (P = 0.036). In univariate survival analysis, high level of expression of PAC-1 mRNA predicted significantly worse overall survival compared to low expression (mean = 30 vs. 52 months, median = 25 vs. 46 months) (P = 0.007).
  
  
  CONCLUSIONS
  Despite the limited size of this cohort, our results present the first evidence supporting a clinical role for PAC-1 in ovarian carcinoma. In view of the improved outcome associated with activation of all three MAPK families, as well as their elevated expression and activation in post-chemotherapy specimens presented in our previous work, they also suggest that PAC-1 is a true negative regulator of MAPK in ovarian carcinoma cells in effusions.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Givant-Horwitz
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.forename: Jeanne Mette
authors.initials: JM
authors.lastname: Goderstad
authors.forename: Jahn M
authors.initials: JM
authors.lastname: Nesland
authors.forename: Claes G
authors.initials: CG
authors.lastname: Tropé
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
mesh_terms: D001202:Ascitic Fluid / Q000201:enzymology; D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D054641:Dual Specificity Phosphatase 2; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D010749:Phosphoprotein Phosphatases; D016066:Pleural Effusion, Malignant / Q000201:enzymology; D011379:Prognosis; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity
chemical_list: D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C517019:DUSP1 protein, human; C517032:DUSP2 protein, human; D054638:Dual Specificity Phosphatase 1; D054641:Dual Specificity Phosphatase 2; D017027:Protein Tyrosine Phosphatases