FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients

Background: epithelial ovarian cancer (eoc) is a spectrum of different diseases,which makes their treatment a challenge. forkhead box m1 (foxm1) is an oncogene aberrantly expressed in many solid cancers including serous eoc,but its role in non-serous eocs remains undefined. we examined foxm1 expression and its correlation to prognosis across the three major eoc subtypes,and its role in tumorigenesis and chemo-resistance in vitro. methods: gene signatures were generated by microarray for 14 clear-cell and 26 endometrioid eocs,and 15 normal endometrium snap-frozen biopsies. validation of foxm1 expression was performed by rt-qpcr and immunohistochemistry in the same samples and additionally in 50 high-grade serous eocs and in their most adequate normal controls (10 luminal fallopian tube and 20 ovarian surface epithelial brushings). correlations of foxm1 expression to clinic-pathological parameters and patients’ prognosis were evaluated by kaplan-meier and cox proportional-hazards analyses. ovcar-3 and two novel deeply characterized eoc cell lines (eoc-cc1 and ospc2,with clear-cell and serous subtype,respectively) were employed for in vitro studies. effects of foxm1 inhibition by transient sirna transfection were evaluated on cell-proliferation,cell-cycle,colony formation,invasion,and response to conventional first- and second-line anticancer agents,and to the parp-inhibitor olaparib. gene signatures of foxm1-silenced cell lines were generated by microarray and confirmed by rt-qpcr. results: a significant foxm1 mrna up-regulation was found in eocs compared to normal controls. foxm1 protein overexpression significantly correlated to serous histology (p = 0.001) and advanced figo stage (p = 0.004). multivariate analyses confirmed foxm1 protein overexpression as an independent indicator of worse disease specific survival in non-serous eocs,and of shorter time to progression in platinum-resistant cases. foxm1 downregulation in eoc cell lines inhibited cell growth and clonogenicity,and promoted the cytotoxic effects of platinum compounds,doxorubicin hydrochloride and olaparib. upon foxm1 knock-down in eoc-cc1 and ospc2 cells,microarray and rt-qpcr analyses revealed the deregulation of several common and other unique subtype-specific foxm1 putative targets involved in cell cycle,metastasis,dna repair and drug response. conclusions: foxm1 is up-regulated in all three major eocs subtypes,and is a prognostic biomarker and a potential combinatorial therapeutic target in platinum resistant disease,irrespective of tumor histology. © 2017 the author(s).