title: The clinical role of the PEA3 transcription factor in ovarian and breast carcinoma in effusions.
abstract: Ets transcription factors play a central role in invasion and metastasis through regulation of synthesis of proteolytic enzymes and angiogenic molecules. The objective of this study was to investigate the role of PEA3 in tumor progression of ovarian and breast carcinoma metastatic to effusions, and to evaluate the expression of Ets-2 and Erg in ovarian carcinoma. Ovarian (83 malignant effusions, 102 corresponding solid lesions) and breast (33 malignant effusions, 40 corresponding solid lesions) carcinomas were evaluated for expression of PEA3 using mRNA in situ Hybridization (ISH). Expression of Ets-2 and Erg mRNA was analyzed in 50 ovarian carcinoma effusions using the same method. PEA3 mRNA expression was comparable at all sites in ovarian carcinoma (44 out of 83; 53% of effusions, 48 out of 102; 47% of solid tumors). PEA3 mRNA expression in effusions correlated with mRNA expression of the previously studied alphav (P = 0.022), alpha6 (P < 0.001) and beta1 (P < 0.001) integrin subunits, the matrix metalloproteinase (MMP) inducer EMMPRIN (P = 0.015) and interleukin-8 (IL-8) (P = 0.033). Erg and Ets-2 mRNA was expressed in 15 out of 50 (30%) and 18 out of 50 (36%) effusions, respectively, and co-localized with PEA3 (P = 0.017 for Erg, P = 0.004 for Ets-2). In breast carcinoma, PEA3 expression was seen in 19/40 (48%) of solid lesions, with a significant upregulation in corresponding effusions compared to primary tumors (24 out of 33; 73%, P = 0.038). PEA3 mRNA expression in effusions obtained prior to the institution of chemotherapy predicted significantly shorter overall survival in univariate analysis (24 vs 37 months, P = 0.03), with a similar trend for Erg (13 vs 30 months, P = 0.1). In conclusion, PEA3 is expressed at all anatomic sites in serous ovarian cancer and co-localizes with Erg, Ets-2 and several metastasis-associated molecules. PEA3 mRNA expression is a novel marker for tumor progression to malignant effusion in breast carcinoma, and predicts poor outcome in effusions sampled prior to therapeutic intervention in ovarian carcinoma. These findings support a biological role for Ets transcription factors in these malignancies and suggests that they may be targets for therapeutic intervention.
authors.affiliation: Department of Pathology, The Norwegian Radium Hospital, Montebello, University of Oslo, Oslo, Norway. davidsob@mail.nih.gov
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.forename: Iris
authors.initials: I
authors.lastname: Goldberg
authors.forename: Liora
authors.initials: L
authors.lastname: Tell
authors.forename: Sophya
authors.initials: S
authors.lastname: Vigdorchik
authors.forename: Mark
authors.initials: M
authors.lastname: Baekelandt
authors.forename: Aasmund
authors.initials: A
authors.lastname: Berner
authors.forename: Gunnar B
authors.initials: GB
authors.lastname: Kristensen
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
authors.forename: Juri
authors.initials: J
authors.lastname: Kopolovic
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000473:pathology / Q000503:physiopathology*; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000071230:Transcriptional Regulator ERG
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C072312:ERG protein, human; C494069:ETS2 protein, human; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C065788:transcription factor PEA3