Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Abstract

BACKGROUND.Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream.METHODS.One hundred twenty‐nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, 11 serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c‐erb‐B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK.RESULTS.Among 129 ovarian neoplasms, 17.8% were positive for c‐erb‐B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p‐AKT), 58.9% were positive for p‐ERK, 41.1% were positive for p‐4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p‐S6. Although EGFR, p‐AKT, and p‐ERK expression did not differ between benign, borderline, or malignant tumors, c‐erb‐B2, p‐4EBP1, p‐p70S6K, and p‐S6 were expressed significantly more often in malignant tumors. Only p‐4EBP1 expression demonstrated prognostic significance (P = .005), and only surgical stage and p‐4EBP1 expression had statistical significance in the multivariate analysis.CONCLUSIONS.In patients with ovarian carcinoma, significant expression of p‐4EBP1 was associated with high‐grade tumors and a poor prognosis, regardless other oncogenic alterations upstream. This finding supports the study of this factor as a hallmark or pivotal factor in cell signaling in ovarian carcinoma that may crucial in the transmission of the proliferation cell signal and may reflect the real oncogenic role of this pathway in ovarian tumors. Cancer 2006. © 2006 American Cancer Society.

Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy

“…This is similar to results found in ovarian cancer, in which differences in the expression of phospho-S6rp and other surrogate markers of mTOR (phospho-4E-BP1, p70S6K) were found in ovarian carcinomas and correlated in a multivariate analysis with high tumor grade and poor prognosis. 24 Immunohistochemical quantitation of our cases nicely stratified into two groups, with a clear separation into low-and high-reactivity sets without knowledge of patient outcome. Of the 11 HE, 8 patients had stable disease (73%) after 2 cycles of treatment with AP23573 alone or in combination with doxorubicin, and of the 9 LE, 6 patients had progressive disease (67%), the differences between which were statistically significant.…”

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

“…Interestingly, those stage IV midgut patients with activated S6K had a reduced disease-specific survival, while this was not true for other downstream effectors or mTOR itself. The detection of p-4EBP1 in the nucleus by us and other groups both in vitro and in vivo is interesting (Zhou et al 2004, Castellvi et al 2006, Rojo et al 2007, Rong et al 2008. It has been demonstrated that the target of 4EBP1, eIF4E, has functions as a nuclear regulator of the export of several RNAs involved in proliferation and cell growth (Culjkovic et al 2007).…”

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

“…9 For example, mTOR can be phosphorylated by other protein kinases, in addition to Akt, 12,34 and the mTOR substrates, S6K and 4E-BP1, can be phosphorylated by Erk1/2. 35 Moreover, signaling pathways are often not unidirectional and may be subject to feedback signaling. Examples include mTOR activation by p-S6K, 34 and Akt inhibition by mTOR.…”