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.
Highlights
Ovarian cancer is the most deadly gynecological malignancy in women, largely due to late diagnosis as tumors have disseminated beyond the ovaries at the diagnosis inover 70% of ovarian cancer patients
To determine if elevated cyclin E1 (CCNE1) expression is linked to CCNE1 gene amplification in ovarian cancer, we initially examined the level of CCNE1 mRNA and protein in a panel of established ovarian cancer cell lines, immortalized ovary epithelial cells (OECs) and fallopian tube secretory epithelial cell (FTSEC)
Level of CCNE1 was elevated in OVCAR3, OVCAR5, OVCAR8 and OCC1 cells compared to that in OECs or FTSECs whereas the remaining cell lines displayed either similar or lower level of CCNE1 compared to OECs and FTSECs (Figure 1A and 1B)
Summary
Ovarian cancer is the most deadly gynecological malignancy in women, largely due to late diagnosis as tumors have disseminated beyond the ovaries at the diagnosis inover 70% of ovarian cancer patients. CCNE1 gene amplification correlates with CCNE1 overexpression in ovarian cancer and appear to have poorer disease-free and overall survival [6] Immunohistochemistry studies with both primary and metastatic ovary tumor specimens further show that the abundance of cyclin E1 (CCNE1) correlates with tumor progression and predicts a poor prognosis in ovarian cancer patients [7,8,9,10]. Taken together, these findings highlight the importance of CCNE1 in ovary tumorigenesis
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