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PEA3 Is the Second Ets Family Transcription Factor Involved in Tumor Progression in Ovarian Carcinoma¹

Department of Pathology, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, University of Oslo, Norway [B. D.]; Department of Pathology [I. G., J. K.] and Division of Gynecologic Oncology [W. H. G., G. B-B.], Sheba Medical Center, Tel-Hashomer 52621, Israel (affiliated with Sackler School of Medicine, Tel-Aviv University); and Department of Pharmacology, Faculty of Medicine, and Center for Pharmacy, Hebrew University, Jerusalem 91120, Israel [R. R.]

Purpose: The purpose of this study was to analyze the possible correlation between PEA3 mRNA expression and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome.

Experimental Design: Sections from 61 primary ovarian carcinomas and metastatic lesions from 36 patients diagnosed with advanced-stage ovarian carcinoma [International Federation of Gynecologists and Obstetricians (FIGO) stages III-IV] were evaluated for expression of PEA3 using mRNA in situ hybridization. Patients were divided into long-term (n = 16) and short-term (n = 20) survivors.

Results: The mean values for disease-free survival and overall survival were 119 and 137 months for long-term survivors, as compared with 4 and 22 months for short-term survivors, respectively. Expression of PEA3 mRNA was detected in carcinoma cells and stromal cells in 56 of 61 lesions (92%) and 54 of 61 lesions (89%), respectively. Intense stromal expression was detected only in the vicinity of grade 2–3 tumors (P = 0.04). PEA3 expression in stromal cells showed a significant association with matrix metalloproteinase 2 mRNA expression in carcinoma cells (P = 0.022). PEA3 expression in carcinoma cells showed an association with mRNA expression of the ß₁ integrin subunit in the same compartment (P = 0.039). It was also associated with mRNA expression of ß₁ integrin subunit (P = 0.012), basic fibroblast growth factor (P = 0.036), and the matrix metalloproteinase inducer EMMPRIN (P = 0.038) in stromal cells. PEA3 mRNA was detected more often in both carcinoma and stromal cells in tumors of short-term survivors (P = 0.021 for stromal cells). In univariate survival analysis, PEA3 expression in stromal cells correlated with both shorter disease-free survival (P = 0.019) and overall survival (P = 0.029), whereas tumor cell expression predicted poor overall survival (P = 0.049). PEA3 mRNA expression in stromal cells emerged as an independent predictor of poor outcome in multivariate survival analysis, in which all molecules previously studied in this patient cohort were included (P = 0.015).

Conclusions: To the best of our knowledge, this is the first evidence associating PEA3 mRNA expression and poor survival in human epithelial malignancy. PEA3 is thus a novel prognostic marker in advanced-stage ovarian carcinoma. The association between PEA3 mRNA expression and the expression of the ß₁ integrin subunit, basic fibroblast growth factor, and EMMPRIN, first documented in our patient cohort, points to the central role of this transcription factor in tumor progression in ovarian carcinoma.

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