Cyclin E mRNA Overexpression in Epithelial Ovarian Cancers: Inverse Correlation with p53 Protein Accumulation

Sawasaki, Takashi; Shigemasa, Kazushi; Shiroyama, Yuko; Kusuda, T.; Fujii, Tsuneo; Parmley, Tim H.; O’Brien, Timothy J.; Ohama, Koso

doi:10.1177/107155760100800310

Cited by 15 publications

(15 citation statements)

References 21 publications

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“…In particular, CCNE1 was shown amplified by FISH analysis in different tumor types including EOCs (Schraml et al, 2003). The overexpression of CCNE1 was observed at the mRNA (30%) and protein (43%) level in ovarian tumors compared to normal ovaries (Sawasaki et al, 2001) and was also associated with a poor prognosis (Rosenberg et al, 2001;Sui et al, 2001a;Farley et al, 2003;Milde-Langosch et al, 2003;Schraml et al, 2003). Moreover, a gradation in CCNE1 expression from benign to LMPs (50%) and to TOVs (70%) has also been reported (Sui et al, 2001a).…”

Section: Discussionmentioning

confidence: 97%

Discrimination between serous low malignant potential and invasive epithelial ovarian tumors using molecular profiling

et al. 2005

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Tumors of low malignant potential (LMP) represent 20% of epithelial ovarian cancers (EOCs) and are associated with a better prognosis than the invasive tumors (TOV). Defining the relationship between LMPs and TOVs remains an important goal towards understanding the molecular pathways that contribute to prognosis, as well as providing molecular markers, for these EOCs. To this end, DNA microarray analyses were performed either in a primary culture or a tumor tissue model system and selected candidate genes showing a distinctive expression profile between LMPs and TOVs were identified using a class prediction approach based on three statistical methods of analysis. Both model systems appear relevant as candidate genes identified by either model allowed the proper reclassification of samples as either LMPs or TOVs. Selected candidate genes (CAS, CCNE1, LGALS8, ITGb3, ATP1B1, FLIP, KRT7 and KRT19) were validated by real-time quantitative PCR analysis and show differential expression between LMPs and TOVs. Immunohistochemistry analyses showed that the two tumor classes were distinguishable by their expression of CAS, TNFR1A, FLIP, CKS1 and CCNE1. These results define signature patterns for gene expression of LMPs and TOVs and identify gene candidates that warrant further study to deepen our understanding of the biology of EOC.

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Section: Discussionmentioning

confidence: 97%

Discrimination between serous low malignant potential and invasive epithelial ovarian tumors using molecular profiling

et al. 2005

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“…Cyclin E (Ccne1) is required for the G1--S phase and has been reported to be over-expressed in many types of cancer. CCNE1 was shown to be over-expressed both at the mRNA and protein level in ovarian tumors compared to normal ovaries 37 and was also associated with a poor prognosis. [19][20][21][22] These results are consistent with those seen in our analysis where Ccne1 represents the most specific marker for distinguishing noninvasive from invasive tumors and it also correlates with the stage of the disease.…”

Section: Discussionmentioning

confidence: 99%

Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

Ouellet

Guyot

Page

et al. 2006

Intl Journal of Cancer

118

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Molecular profiling is a powerful approach to identify potential clinical markers for diagnosis and prognosis as well as providing a better understanding of the biology of epithelial ovarian cancer. On the basis of the analysis of HuFL expression data, we have previously identified genes that distinguish low malignant potential and invasive serous epithelial ovarian tumors. In this study, we used immunohistochemistry to monitor a subset of differently expressed candidates (Ahr, Paep, Madh3, Ran, Met, Mek1, Ccne1, Ccd20, Cks1 and Cas). A tissue array composed of 244 serous tumors of different grades (0–3) and stages (I–IV) was used in this analysis. All markers assayed presented differential protein expression between serous tumors of low and high grade. Significant differences in Ccne1 and Ran expression were observed in a comparison of low malignant potential and grade 1 tumor samples (p < 0.01). In addition, irrespective of the grade, Ccne1, Ran, Cdc20 and Cks1 showed significant differences of expression in association with the clinical stage of disease. While high level of Ccne1 have previously been associated with poor outcomes, here we found that high level of either Ran or Cdc20 appear to be more tightly associated with a poor prognosis (p < 0.001, 0.03, respectively). The application of these biomarkers in both the initial diagnosis and prognostic attributes of patients with epithelial ovarian tumors should prove to be useful in patient management. © 2006 Wiley‐Liss, Inc.

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“…In fact, we have shown that in both normal and tumor cells, at the level of RNA, cyclin E is present as multiple splice variants; however, these splice variants do not give rise to protein products (16). Therefore, it seems that the primary process that contributes to deregulation of cyclin E is through posttranslational proteolytic cleavage of the full-length protein by elastase, which results in generation of the low molecular weight (LMW) forms (17).In ovarian cancer, cyclin E gene amplification has been described in 12% to 21% of ovarian tumors (7, 18) with RNA overexpression reported in as many as 30% of cases (7,18,19) and up to 70% of tumors are reported to show overexpression at the protein level (20,21). Of note, all the studies of cyclin E protein expression have relied on immunohistochemical techniques that may not be as sensitive as Western blot analysis for the overexpression and detection of the LMW form of this cell cycle regulator (12).…”

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confidence: 99%

“…In ovarian cancer, cyclin E gene amplification has been described in 12% to 21% of ovarian tumors (7, 18) with RNA overexpression reported in as many as 30% of cases (7,18,19) and up to 70% of tumors are reported to show overexpression at the protein level (20,21). Of note, all the studies of cyclin E protein expression have relied on immunohistochemical techniques that may not be as sensitive as Western blot analysis for the overexpression and detection of the LMW form of this cell cycle regulator (12).…”

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Cyclin E–Associated Kinase Activity Predicts Response to Platinum-Based Chemotherapy

Bedrosian

Lee

Tucker³

et al. 2007

Clinical Cancer Research

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Purpose: The role of cyclin E as a predictive marker of response to chemotherapy remains unknown. We have previously shown that deregulation of cyclin E in an ovarian tumor cell line model enhances cyclin E^associated kinase activity and sensitizes tumor cells to cisplatinum. We hypothesized that cyclin E deregulation would predict for responsiveness to platinum-based regimens in ovarian cancer patients. Experimental Design: Patients who met the following criteria were retrospectively identified from the institutional tumor bank records: (a) high-grade ovarian epithelial malignancy, (b) stage III/stage IV disease, (c) optimally debulked, (d) completed platinum-based therapy. Tumor samples were analyzed for cyclin E, p21, and p27 byWestern blot analysis and assessed for cyclin E^associated kinase activity. Results: Seventy-five patients, who met the study criteria, were identified. Cyclin E protein levels did not correlate with cyclin E^cdk2 kinase activity (Spearman's rho, 0.07; P = 0.58). Cyclin E^associated kinase activity was the only significant predictive marker for response to platinum-based therapy, with higher response rates seen in patients with higher levels of activity (P = 0.045). Cyclin E protein levels did not predict for platinum sensitivity (P = 0.20). In contrast, cyclin E protein levels, but not cyclin E^associated kinase activity, was a significant predictor for freedom from recurrence (P = 0.01and P = 0.25, respectively). Conclusions: Cyclin E overexpression and cyclin E^associated kinase activity have distinct roles in predicting for response to chemotherapy and outcome in ovarian cancer patients. These results suggest a compartmentalization of cyclin E functions in the oncogenic process.Overexpression of the cyclin E protein has been linked to shortening of the G 1 phase of the cell cycle (1), decreased requirement for growth factors (1), enhanced cell proliferation (2), induction of chromosomal instability (3, 4), and polyploidy (5). These processes contribute toward the oncogenic potential of cyclin E. Most importantly, cyclin E protein levels have been shown to correlate with a more aggressive tumor phenotype and adverse prognosis in a number of malignancies including breast, ovarian, gastric, non -small cell, and adrenocortical carcinomas, as well as non-Hodgkin's lymphoma (6-15).The major form of deregulation of cyclin E is at the level of protein. In examining cyclin E deregulation in breast cancer, we have previously published that irrespective of whether or not the gene is amplified (which occurs only in 10% of all breast cancer cases), the protein is independently deregulated. In fact, we have shown that in both normal and tumor cells, at the level of RNA, cyclin E is present as multiple splice variants; however, these splice variants do not give rise to protein products (16). Therefore, it seems that the primary process that contributes to deregulation of cyclin E is through posttranslational proteolytic cleavage of the full-length protein by elastase, which results in ge...

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Cyclin E mRNA Overexpression in Epithelial Ovarian Cancers: Inverse Correlation with p53 Protein Accumulation

Abstract: Cyclin E mRNA overexpression frequently occurs in ovarian cancers without p53 protein accumulation. Cyclin E might have an important effect on the development of a limited number of ovarian cancers.

Cited by 15 publications

References 21 publications

Discrimination between serous low malignant potential and invasive epithelial ovarian tumors using molecular profiling

Discrimination between serous low malignant potential and invasive epithelial ovarian tumors using molecular profiling

Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

Cyclin E–Associated Kinase Activity Predicts Response to Platinum-Based Chemotherapy

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