GENES, CHROMOSOMES & CANCER 51:300–312 (2012) EGR1 and FOSB Gene Expressions in Cancer Stroma Are Independent Prognostic Indicators for Epithelial Ovarian Cancer Receiving Standard Therapy Fumio Kataoka, 1 Hiroshi Tsuda, 1 * Tokuzo Arao, 2 Sadako Nishimura, 3 Hideo Tanaka, 1 Hiroyuki Nomura, 1 Tatsuyuki Chiyoda, 1 Akira Hirasawa, 1 Tomoko Akahane, 1 Hiroshi Nishio, 1 Kazuto Nishio, 2 and Daisuke Aoki 1 1 Department of Obstetrics and Gynecology, School of Medicine,Keio University,Tokyo, Japan 2 Department of Genome Biology,Kinki University School of Medicine,Osaka, Japan 3 Department of Obstetrics and Gynecology,Osaka City General Hospital,Osaka, Japan Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to iden- tify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy- four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immuno- histochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and a-smooth muscle actin positive stromal fibro- blasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC. V V C 2011 Wiley Periodicals, Inc. INTRODUCTION Epithelial ovarian cancer (EOC) is a common cause of cancer death in women. Early diagnosis of EOC is difficult because of a lack of specific symptoms so that 80% of patients are diagnosed at Stage III or IV. EOC is a relatively chemosen- sitive tumor, and 70% of advanced EOC (aEOC) patients treated by standard surgical procedures (bilateral adnexectomy þ hysterectomy þ greater omentectomy) with staging laparotomy and debulking surgery, followed by postoperative chemotherapy using a combination of platinum and taxan, achieved a complete clinical response. However, disease recurs in most patients within 2 years after diagnosis and death is due to chemo- therapy-resistant tumor. If reliable predictive markers could be established, patients who are likely to relapse and die of disease are good can- didates for clinical trials using new drugs. We previously reported that the amplification of 8q24 and 20q11-13 or 17q21-q24 can predict progres- sion-free survival (PFS) in EOC and may be new predictive biomarkers for aEOC (Hirasawa et al., 2003; Tominaga et al., 2010). Cancer consists of founder cancer cells and stroma, including blood and lymph endothelial cells, inflammatory cells, immunocytes, macrophages and fibroblasts. Stroma is thought to play a role in tumor behav- ior, including invasion or metastasis and response to therapy (Bhowmick and Moses, 2005; Kim et al., 2005; Tlsty and Coussens, 2006). However, the role of stromal cells in the development and progression of epithelial neoplasia has not been thoroughly investigated. Finak et al. used laser capture micro- dissection (LCM) to compare gene expression pro- files of tumor stroma from 53 primary breast cancers and established a new stroma-derived prog- nostic predictor (SDPP) that stratifies disease out- come independently of standard clinical prognostic factors or published gene expression-based predic- tors (Finak et al., 2008). However, few studies have examined the tumor–stroma interaction in clinical Additional Supporting Information may be found in the online version of this article. Supported by: Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science and Culture, Japan, Grant number: 20014024; A Grant-in Aid for scientific Research (C) from the Ministry of Education, Science and Culture, Japan; Grant number: 19591940; Osaka City General Hospital. *Correspondence to: Hiroshi Tsuda, MD, PhD, Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan. Tel.: þ81-3-3353-1211 (Ext 61721). Fax: þ81-3-3353-0249. E-mail: htsud@s5.dion.ne.jp Received 20 June 2011; Accepted 27 October 2011 DOI 10.1002/gcc.21916 Published online 15 November 2011 in Wiley Online Library (wileyonlinelibrary.com). V V C 2011 Wiley Periodicals, Inc.