Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer

Abstract

BACKGROUND: This study examined the clinical significance of CCNE1 (Cyclin E1) amplification and assessed whether CCNE1 is a potential therapeutic target in ovarian cancer. METHODS: CCNE1 expression and amplification in ovarian cancer was assessed by immunohistochemistry, fluorescence in situ hybridization and clinical data collected by retrospective chart review. CCNE1 gene knockdown using silencing RNA and a CCNE1 gene transfection system were used to asses CCNE1 function in tissue samples of ovarian cancer. RESULTS: Gene amplification was identified in 18 (20.4%) of 88 ovarian carcinomas. CCNE1 copy number significantly correlated with CCNE1 protein expression (r ¼ 0.522, P < .0001). CCNE1 amplification significantly correlated with shorter disease-free survival and overall survival (P < .001). There were nonsignificant trends between high protein expression and poor disease-free survival (P ¼ .2865) and overall survival (P ¼ .1248). Multivariate analysis showed gene amplification was an independent prognostic factor for disease-free survival and overall survival after standard platinum-taxane chemotherapy (P ¼ .0274, P ¼ .0023). Profound growth inhibition and apoptosis were observed in silencing RNA-treated cancer cells with gene amplification compared with results in cancer cells with CCNE1 moderate expression without gene amplification or with low CCNE1 expression. CCNE1 overexpression stimulated proliferation in ovarian cancer cell lines ES2 and TOV-21G, which have lower endogenous CCNE1 expression. CONCLUSIONS: These findings indicate that CCNE1 overexpression is critical to growth and survival of ovarian cancer tumors with CCNE1 gene amplification. Furthermore, they suggest that CCNE1 silencing RNA-induced phenotypes depend on amplification status of ovarian cancers. Therefore, CCNE1-targeted therapy may benefit ovarian cancer patients with CCNE1 amplification.

Frequent CCNE1 amplification in endometrial intraepithelial carcinoma and uterine serous carcinoma

“…For example, in breast and ovarian cancers, in vitro silencing of CCNE1 suppresses cellular growth selectively in cells harboring CCNE1 amplification. 10,18,19 On the other hand, ectopic expression of CCNE1 increases cellular proliferation in ovarian cancer cell lines. 18 Moreover, these data support the driver role of CCNE1 amplification in cancers as cyclin E1 mediates G1/S transition through the activation of CDK2.…”

“…10,18,19 On the other hand, ectopic expression of CCNE1 increases cellular proliferation in ovarian cancer cell lines. 18 Moreover, these data support the driver role of CCNE1 amplification in cancers as cyclin E1 mediates G1/S transition through the activation of CDK2. Interestingly, the survival of breast cancer cells harboring CCNE1 gene amplification depends on CDK2 expression and kinase activity.…”

Gene Amplification in Ovarian Carcinomas: Lessons from Selected Amplified Gene Families

“…The association between cyclin E amplification and poor outcome has also been identified in recent German and Japanese studies, although the correlation was not statistically significant in the latter (Mayr et al 2006, Nakayama et al 2010. Two independent labs have also suggested that amplification of the cyclin E gene was associated with primary treatment resistance and targeting cyclin E expression with siRNA reduced cell viability and increased apoptosis (Etemadmoghadam et al 2009, Nakayama et al 2010. These studies suggest that cyclin E amplification/expression may serve as both a prognostic and predictive factor in ovarian cancer as well as a therapeutic target in the treatment of ovarian cancer.…”

“…Analysis of the subset of patients with serous carcinomas (72% of total study) showed an 11 month difference in median survival and suggested that the role of cyclin E was limited to the serous histology as nonserous tumors showed no statistically significant difference in survival based on cyclin E expression. The association between cyclin E amplification and poor outcome has also been identified in recent German and Japanese studies, although the correlation was not statistically significant in the latter (Mayr et al 2006, Nakayama et al 2010. Two independent labs have also suggested that amplification of the cyclin E gene was associated with primary treatment resistance and targeting cyclin E expression with siRNA reduced cell viability and increased apoptosis (Etemadmoghadam et al 2009, Nakayama et al 2010.…”

“…Studies in epithelial ovarian cancer have shown inconsistent associations between individual cell cycle regulatory protein expression and patient outcome (reviewed in Nam and Kim (Nam and Kim 2008)). Among the best studied in ovarian cancer is cyclin E. Amplification of the cyclin E gene occurs in 7-65% of ovarian cancers, typically resulting in overexpression of the cyclin E protein (Cancer Genome Atlas Research Network, 2011, Courjal et al 1996 1998, Mayr et al 2006, Nakayama et al 2007, Nakayama et al 2010, Schraml et al 2003a. Cyclin E expression has been found in as many as 97% of ovarian cancer/primary peritoneal cancer samples .…”