Figure 2.

Targeting cyclin E1-dependent ovarian cancers. (A) Cyclin E1 function is dependent on it interaction with CDK1 and CKD2. CDK1/2 inhibitors inhibit this interaction and cause E2F-mediated transcriptional downregulation of BRCA1 and BRCA2. CDK1/2 inhibition may also prevent their phosphorylation and subsequent activation of the BRCA1 and BRCA2 proteins. Alternatively, use of Bortezomib, a proteasomal inhibitor, can inhibit HR function and potentially sensitize cyclin E1-dependent tumors to platinum-based chemotherapy. NLS, nuclear localization signal; BRCT, BRCA1 C-terminus domain. (B) Kaplan–Meier curve showing that CCNE1 overexpression (n = 32 tumors, Z-score ≥ 2) in HGSOC was associated with significantly reduced overall survival (OS) as compared with tumors with normal or low expression of CCNE1 (n = 97 tumors, Z-score < 2). Median OS for cancers with CCNE1 high and normal/low expression were 33.44 and 47.47 months, respectively. A subset of 129 HGSOC tumors from the TCGA dataset was used for this analysis and was selected based on p53-mutant and BRCA1- and BRCA2-wildtype status as well as availability of RNAseq V2 data. Data were accessed using the cBioPortal for Cancer Genomics maintained by the Computational Biology Center at Memorial Sloan-Kettering Cancer Center. (C) Increased expression of HR and DNA repair-related genes in cyclin E1-overexpressing tumors. Known E2F targets, E2F1, BIRC5 (survivin), CDK1 (CDC2), and TK1 are included for reference. Median Z-score values for each CCNE1 expression subset are shown; P values were determined using Student’s t-test.