Cyclin-dependent kinase 2 is an ideal target for ovary tumors with elevated cyclin E1 expression

Abstract

CCNE1 gene amplification is present in 15-20% ovary tumor specimens. Here, we showed that Cyclin E1 (CCNE1) was overexpressed in 30% of established ovarian cancer cell lines. We also showed that CCNE1 was stained positive in over 40% of primary ovary tumor specimens regardless of their histological types while CCNE1 staining was either negative or low in normal ovary and benign ovary tumor tissues. However, the status of CCNE1 overexpression was not associated with the tumorigenic potential of ovarian cancer cell lines and also did not correlate with pathological grades of ovary tumor specimens. Subsequent experiments with CCNE1 siRNAs showed that knockdown of CCNE1 reduced cell growth only in cells with inherent CCNE1 overexpression, indicating that these cells may have developed an addiction to CCNE1 for growth/survival. As CCNE1 is a regulatory factor of cyclin-dependent kinase 2 (Cdk2), we investigated the effect of Cdk2 inhibitor on ovary tumorigenecity. Ovarian cancer cells with elevated CCNE1 expression were 40 times more sensitive to Cdk2 inhibitorSNS-032 than those without inherent CCNE1 overexpression. Moreover, SNS-032 greatly prolonged the survival of mice bearing ovary tumors with inherent CCNE1 overexpression. This study suggests that ovary tumors with elevated CCNE1 expression may be staged for Cdk2-targeted therapy.