Mammalian target of rapamycin is a biomarker of poor survival in metastatic serous ovarian carcinoma☆
Received 29 May 2009; received in revised form 28 August 2009; accepted 22 September 2009. published online 15 February 2010.
Summary
The AKT signaling pathway is crucial for cancer cell survival. The objective of this study was to analyze the expression and clinical role of this pathway in serous ovarian carcinoma. Phospho-AKT and phospho–mammalian target of rapamycin protein expression was studied in 269 ovarian carcinomas (159 effusions, 38 primary carcinomas, 72 solid metastases) using immunohistochemistry. The association between AKT, mammalian target of rapamycin, and DJ-1 in effusions was quantitatively analyzed using flow cytometry. AKT phosphorylation status in effusions was further studied using Western blotting. Phospho-AKT and phospho–mammalian target of rapamycin were detected in the majority of tumors at all anatomical sites. Phospho-AKT expression in effusions was higher in grade 3 versus grades 1 and 2 tumors (P = .013). Flow cytometry analysis showed association between AKT, mammalian target of rapamycin, and DJ-1 expression (P < .001). Higher phospho-AKT Thr308/pan-AKT ratio by Western blotting was associated with more advanced International Federation of Gynecology and Obstetrics stage (P = .018) and a trend for poor response to chemotherapy at first disease recurrence (P = .051). Higher phospho–mammalian target of rapamycin protein expression in effusions by immunohistochemistry was associated with poor progression-free survival for patients with postchemotherapy effusions (P = .005). Phospho–mammalian target of rapamycin was an independent predictor of poor progression-free survival for patients with postchemotherapy effusions (P = .03). The association between activated AKT and mammalian target of rapamycin expression and clinicopathologic parameters of aggressive disease, including shorter patient survival, provides further evidence regarding the central role of this signaling pathway in ovarian carcinoma.
aDivision of Obstetrics and Gynecology, Section for Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway
bDivision of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway
cDepartment of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
dFaculty Division Radiumhospitalet, the Medical Faculty, University of Oslo, N-0316 Oslo, Norway
Corresponding author. Department of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Montebello, N-0310 Oslo, Norway.
☆ Financial acknowledgement: This work was supported by grants from the Norwegian Cancer Society (Olso, Norway), the Health Region of South-Eastern Norway (Hamar, Norway), and the Inger and Jon Fredriksen Foundation for Ovarian Cancer Research (Olso, Norway).