The mTOR downstream regulator (p-4EBP1) is a novel independent prognostic marker in ovarian cancer

Abstract

Ovarian cancer is associated with the highest mortality rate among gynaecologic malignancies. There is a need to refine the classification of ovarian cancer and identify novel targets. The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. This study aims to investigate the prognostic role of p-mTOR and its major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer. p-mTOR, p-4EBP1 and p-P70S6K protein expression was assessed on 195 consecutive ovarian epithelial cancers and correlated to clinicopathological features and survival. We found that high cytoplasmic expression of p-4EBP1 and p-P70S6K was associated with a serous type carcinoma (p = .005) and an advanced FIGO stage (p = .012), respectively. Univariate outcome analysis showed an inverse association between a high expression of p-4EBP1 expression and overall ovarian cancer survival (OS; p = .005) and progression-free survival (PFS; p = .005). p-P70S6K showed an inverse association with PFS (p = .001). Multivariate analyses indicated that p-4EBP1 was an independent predictor of both OS and PFS (p = .016 and p = .041, respectively). Therefore, we concluded that p-4EBP1 high protein expression is an independent predictor of outcome in ovarian cancer patients. Therefore, it could be used as a potential biomarker for prognostic stratification and treatment decisions.

Impact statement

• What is already known on this subject? The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. To-date, very limited knowledge is known about the importance of mTOR major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer.

• What do the results of this study add? In this study, we have provided further evidence of the adverse prognostic behaviour associated with the positive expression of p-mTOR and its major downstream effectors. Moreover and by performing multivariate analysis, we for the first time have proved that p-4EBP1 is an independent predictor of clinical outcome in ovarian cancer.

• What are the implications of these findings for clinical practice and/or further research? p-4EBP1 could be used as a potential biomarker for prognostic stratification and treatment decisions in ovarian cancer management.

Keywords:

• Ovarian cancer
• p-mTOR
• survival

Disclosure statement

No potential conflict of interest was reported by the authors.