Mammalian target of rapamycin is a biomarker of poor survival in metastatic serous ovarian carcinoma.
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.
Division of Obstetrics and Gynecology, Section for Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway.
Mari
M
Bunkholt Elstrand
Hiep Phuc
HP
Dong
Elin
E
Ødegaard
Arild
A
Holth
Sivan
S
Elloul
Reuven
R
Reich
Claes G
CG
Tropé
Ben
B
Davidson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001202:Ascitic Fluid / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D018293:Cystadenoma, Serous / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008875:Middle Aged; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000556:secondary; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D016066:Pleural Effusion, Malignant / Q000378:metabolism; D011379:Prognosis; D000071617:Protein Deglycase DJ-1; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases
D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D010750:Phosphoproteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1