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In the oncogenic process, cell growth control plays a crucial role, and growth factor receptors and their signaling pathways are known to be altered in endometrial cancer, mostly in type I carcinomas. Two main pathways are involved in transmitting the proliferative signal from the membrane receptors to the nucleus: phosphatydil-inositol-3-kinase-protein kinase B-mammalian target of rapamycin and RAS-RAF-ERK pathways. A final effector of these signaling cascades is the cap-dependent mRNA translation initiation complex, which is negatively regulated by 4E-BP1. The aim of our work was to study the relative importance of the factors involved in these pathways and to see their correlation with the clinicopathologic features of the tumors and their prognosis. We studied 120 endometrial carcinomas, including 93 type I and 27 type II carcinomas, and 18 control cases. Tissue microarrays were constructed and immunohistochemistry was performed for HER2, p53, and the phosphorylated forms of protein kinase B, extracellular signal-regulated kinase, and 4E-BP1. HER2 was overexpressed in 11% of carcinomas but not in control cases, and 30% of carcinomas showed activation of protein kinase B and extracellular signal-regulated kinase, mostly in type II carcinomas. The phosphorylated form of 4E-BP1 was found to be cytoplasmic in 31% of cases, and in 63% of cases it showed nuclear expression; the latter was only found in carcinomas. p53 positivity was found in type II and in grade 3 type I carcinomas. This nuclear expression of phospho-4E-BP1 and HER2 overexpression were the only characteristics with prognostic significance. The activation of the signaling pathways that control cell growth is a common event in endometrial carcinomas. 4E-BP1 is a downstream effector of these pathways whose activation status correlates with aggressive phenotypes and prognosis. This factor can reflect the activity of these pathways, regardless of the upstream molecular alterations, and, therefore, it can be a hallmark of the transmission of the oncogenic signal to the nucleus.

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., (2006 American Cancer Society)