1. ¹Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia
2. ²St Vincent's Clinical School, University of NSW, Sydney, New South Wales, Australia
3. ³South East Area Laboratory Service, Prince of Wales Hospital, Randwick, Sydney, New South Wales 2031, Australia
4. ⁴Division of Gynecology, University Hospital Zurich, 8091 Zurich, Switzerland
5. ⁵Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia
6. ⁶Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Melbourne, Victoria 3168, Australia
7. ⁷Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead, Sydney, New South Wales 2145, Australia
8. ⁸Department of Gynaecological Oncology, Westmead Hospital, Westmead, Sydney, New South Wales 2145, Australia
9. ⁹Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90089, CA, USA
10. ¹⁰Gynaecological Cancer Centre, Royal Hospital for Women, Randwick, Sydney, New South Wales 2031, Australia
11. ¹¹School of Women's and Children's Health, University of NSW, Sydney, New South Wales, Australia

Correspondence: Dr PM O'Brien, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales (NSW) 2010, Sydney, Australia. E-mail: p.obrien@garvan.org.au

Received 26 November 2007; Revised 29 January 2008; Accepted 29 January 2008.

Abstract

Despite a high initial response rate to first-line platinum/paclitaxel chemotherapy, most women with epithelial ovarian cancer relapse with recurrent disease that becomes refractory to further cytotoxic treatment. We have previously shown that the E3 ubiquitin ligase, EDD, a regulator of DNA damage responses, is amplified and overexpressed in serous ovarian carcinoma. Given that DNA damage pathways are linked to platinum resistance, the aim of this study was to determine if EDD expression was associated with disease recurrence and platinum sensitivity in serous ovarian cancer. High nuclear EDD expression, as determined by immunohistochemistry in a cohort of 151 women with serous ovarian carcinoma, was associated with an approximately two-fold increased risk of disease recurrence and death in patients who initially responded to first-line chemotherapy, independently of disease stage and suboptimal debulking. Although EDD expression was not directly correlated with relative cisplatin sensitivity of ovarian cancer cell lines, sensitivity to cisplatin was partially restored in platinum-resistant A2780-cp70 ovarian cancer cells following siRNA-mediated knockdown of EDD expression. These results identify EDD as a new independent prognostic marker for outcome in serous ovarian cancer, and suggest that pathways involving EDD, including DNA damage responses, may represent new therapeutic targets for chemoresistant ovarian cancer.