We have found that EEF1A2, the gene encoding protein elongation factor EEF1A2 (also known as eEF-1 alpha 2), is amplified in 25% of primary ovarian tumors and is highly expressed in approximately 30% of ovarian tumors and established cell lines. We have also demonstrated that EEF1A2 has oncogenic properties: it enhances focus formation, allows anchorage-independent growth and decreases the doubling time of rodent fibroblasts. In addition, EEF1A2 expression made NIH3T3 fibroblasts tumorigenic and increased the growth rate of ES-2 ovarian carcinoma cells xenografted in nude mice. Thus, EEF1A2 and the process of protein elongation are likely to be critical in the development of ovarian cancer.
Abnormalities in G1/S transition in cell cultures have been attributed to alterations in ErbB (erythroblastic leukaemia viral [v-erb-b] oncogene homologue, avian) signalling, cyclin D1 overexpression or disturbance of the p21(WAF1) (p21)-mediated cell cycle arrest induced by p53. To investigate the significance of these mechanisms on an early stage of human breast tumour growth, we studied the expression of EGFR (ErbB1), HER-2/neu (ErbB2), cyclin D1, p21 and p53 as well as oestrogen (ER) and progesterone receptor (PgR) in paraffin sections of 45 ductal carcinoma in situ (DCIS) by immunohistochemistry. Cell proliferation was assessed by immunohistochemical quantification of Ki-67. Five cases with cyclin D1 overexpression were analysed by FISH for CCND1 amplification. Increased proliferative activity was observed in 46% of DCIS. It was correlated with the expression of EGFR and HER-2/neu (p < 0.05), but neither with cyclin D1 and p21 overexpression nor with p53 accumulation. ErbB positive status was associated with p21 overexpression (p < 0.05). In addition we found a correlation between the overexpression of p21 and cyclin D1 restricted to ErbB-positive cases (p = 0.013). ErbB-negative tumours with increased proliferative activity were ER and cyclin D1 positive. No CCND1 amplification was detected in the analysed cases. In conclusion, our data support that EGFR and HER-2/neu play an important role in cell cycle control in DCIS. p21 appears to be a potential mediator of ErbB signalling. We propose that cyclin D1 could be indirectly induced by ErbB signalling through p21. Besides, ER-mediated upregulation of cyclin D1 seems to be a possible mechanism of maintaining cell proliferation in DCIS in case of EGFR- and HER-2/neu-negativity.
To identify oncogene amplification involved in ovarian carcinogenesis, we studied 21 ovarian carcinomas and 5 serous borderline tumors using conventional comparative genomic hybridization (CGH) and CGH to a genomic DNA microarray. Immunohistochemical analysis of the proteins encoded by the genes that were amplified frequently (FGF3/4, FGFR1, CCNE1, PAK1, JUNB, and MDM2) was performed on a tissue microarray comprising 254 cases of ovarian neoplasms. Regarding histologic type, characteristic patterns of copy number changes were revealed. They correlated with histologic tumor type and with intratumoral heterogeneity. Gain of FGF3/4 and CCNE1 was found in all serous carcinomas. Endometrioid carcinomas most frequently showed gain of JUNB (83%), KRAS2 (67%), MYCN (50%), ESR (50%), and CCND2 (50%). Of the serous borderline tumors, 80% harbored amplification of FGFR1 and MDM2 and a 75% gain of PIK3CA. Only CCNE1 immunoreactivity was significantly correlated with CGH results (P < .05) and postoperative survival (P < .05). Microarray-based genomic analysis in combination with immunohistochemical analysis was found to be a powerful technique for identification of clinically relevant gene amplification in human ovarian cancer.
TMA is a feasible tool to study a large number of ovarian cases. Correlation between immunohistochemistry and FISH was excellent. HER-2/neu overexpression or gene amplification does not correlate with histological tumour type, stage, grade or prognosis.
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