Master of Science (MS)
Dr. Adam Karpf
High-grade serous ovarian cancer (HGSC) ranks as the fifth leading cause of female cancer related deaths. A greater understanding of the molecular mechanisms underlying HGSC will elucidate better detection methods and identify potential treatment targets.
Forkhead Box M1 (FOXM1) is a key player in HGSC, as data from The Cancer Genome Atlas (TCGA) revealed that its activation is the second most frequent molecular alteration in HGSC. Similarly, cyclin E1 (CCNE1) is also important in HGSC, as the gene is amplified in 20% of HGSC cases. Both genes and proteins have been studied extensively, but the potential interaction between the two has not been examined in HGSC progression or in other cancer models.
We found that dual ectopic expression of CCNE1 and FOXM1 leads to phosphorylation of FOXM1 in a HGSC cell precursor model [fallopian tube epithelial (FTE) cells] at residue threonine 600, contributing to activation of FOXM1. Our studies reveal that the reaction is mediated primarily through the CCNE1 and cyclin dependent kinase (CDK) 2 complex. Importantly, transformation assays revealed that CCNE1 and FOXM1 contribute to FTE cell proliferation, migration, and invasion in a cooperative manner.
Further evidence for a functional interaction between CCNE1 and FOXM1 was observed in HGSC lines. Phosphorylated FOXM1 (p-FOXM1) was found in HGSC cell lines and primary epithelial ovarian carcinoma (EOC) tumor samples. In primary EOC tumor samples, CCNE1, FOXM1, and CDK2 correlate strongly with p-FOXM1 expression. Treatment with a CDK2 inhibitor, dinaciclib, resulted in a marked decrease of p-FOXM1 in a FTE and HGSC model, validating CDK2 as a critical factor in FOXM1 phosphorylation.
Elge, Lucy, "Cooperativity of CCNE1 and FOXM1 in High-Grade Serous Ovarian Cancer" (2020). Theses & Dissertations. 480.