Ets-1 Messenger RNA Expression Is a Novel Marker of Poor Survival in Ovarian Carcinoma See The Biology Behind: D. G. Gilliland, The Diverse Role of the ETS Family of Transcription Factors in Cancer. Clin. Cancer Res., 7: 451– 453, 2001. Ben Davidson, 1 Reuven Reich, Iris Goldberg, Walter H. Gotlieb, Juri Kopolovic, Aasmund Berner, Gilad Ben-Baruch, Magne Bryne, and Jahn M. Nesland Department of Pathology, The Norwegian Radium Hospital, Montebello N-0310 Oslo, Norway, affiliated with the University of Oslo, Oslo N-0216 Norway [B. D., A. B., J. M. N.]; Department of Pharmacology, Faculty of Medicine and David R. Bloom Center for Pharmacy, Hebrew University, Jerusalem 91120, Israel [R. R.]; 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 Oral Biology, University of Oslo, Oslo, Norway [M. B.] ABSTRACT Ets-1 proto-oncogene is a transcription factor involved in several cellular functions, including the activation of sev- eral proteases participating in tumor invasion and metasta- sis. The objective of this study was to analyze the possible correlation between Ets-1 mRNA expression and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome. Sections from 66 primary ovarian carcinomas and metastatic lesions from 41 patients diagnosed with advanced-stage ovarian carcinoma (International Federation of Gynecologists and Obstetricians stages III and IV) were evaluated for expres- sion of Ets-1 using mRNA in situ hybridization. Patients were divided into long-term (n  17) and short-term (n  24) survivors. The mean values for disease-free survival and overall survival were 116 and 133 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Expression of Ets-1 mRNA was de- tected in carcinoma cells and stromal cells in 28 of 66 (42%) and 22 of 66 (33%) lesions, respectively. Ets-1 expression showed an association with mRNA expression of vascular endothelial growth factor (P  0.001 for carcinoma cells; P  0.004 for stromal cells), basic fibroblast growth factor (P  0.049 for carcinoma cells), and membrane type-1 ma- trix metalloproteinase (P  0.045), which were previously studied in this patient cohort. Ets-1 mRNA was detected more often in both carcinoma and stromal cells in tumors of short-term survivors (P  0.038 for carcinoma cells). In univariate survival analysis for all cases, Ets-1 expression in both tumor (P  0.018) and stroma (P  0.026) correlated with poor survival. These findings were reproduced in an analysis of primary tumors alone (P  0.039 for tumor cells; P < 0.001 for stromal cells). Ets-1 mRNA expression in stromal cells retained its predictive power in a multivariate survival analysis in which all molecules studied previously in this patient cohort were included (P  0.007). To our knowl- edge, this is the first evidence associating Ets-1 mRNA ex- pression and poor survival in human epithelial malignancy. Ets-1 is thus a novel prognostic marker in advanced-stage ovarian carcinoma. The association between Ets-1 mRNA expression and the expression of membrane type-1 matrix metalloproteinase and angiogenic genes, first documented here in a study of patient material, points to the central role of this transcription factor in tumor progression in ovarian carcinoma. INTRODUCTION The majority of malignant solid tumors lead to death of the host through tumor dissemination, involving both local invasion and subsequent spread to distant organs. Both processes depend on the elaboration of various molecules by tumor and stromal cells. Two of the major classes of cancer-associated molecules are matrix-degrading proteases and angiogenic factors (1, 2). The ets oncogene (v-ets) was discovered as part of a fusion protein with gag and myb expressed by the E26 avian erythro- blastosis virus (3). The Ets family of transcription factors is divided into subfamilies (Ets-1 and -2, ERG, GABP, PEA3, ELK, ELF, and PU1), based mainly on the sequence and loca- tion of the Ets domain, an 84-amino acid sequence present in all members of the family. Ets proteins bind to DNA sequences having the core motif C/AGCAA/T (4). Ets transcription factors play a role in a variety of physi- ological and pathological process, including embryogenesis, wound healing, and tumor progression (4, 5). This is largely due to their ability to activate the transcription of several proteases, including urokinase-type plasminogen activator, collagenase I (MMP-1 2 ), stromelysin I (MMP-3), and gelatinase B (MMP-9; Received 8/31/00; accepted 11/20/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Department of Pathology, The Norwegian Radium Hospital, Montebello N-0310, Oslo, Norway. Phone: 47-22934871; Fax: 47-22508554; E-mail: bend@ulrik. uio.no. 2 The abbreviations used are: MMP, matrix metalloproteinase; MT, membrane type; ISH, in situ hybridization; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; TIMP, tissue in- hibitor of metalloproteinase. 551 Vol. 7, 551–557, March 2001 Clinical Cancer Research Research. on October 23, 2021. © 2001 American Association for Cancer clincancerres.aacrjournals.org Downloaded from