Abstract
BackgroundEpithelial 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.MethodsGene 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.ResultsA 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.ConclusionsFOXM1 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.
Highlights
Epithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge
Forkhead box M1 (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
FOXM1 was consistently overexpressed in clear-cell, endometrioid and high grade serous EOC subtypes Comprehensive gene expression profiles of 40 EOC specimens of two different histological patterns (26 endometrioid and 14 clear-cell EOCs), and of their relative normal counterpart (15 normal endometrium) were generated using high-density oligonucleotide microarrays, with the aim to identify subtype-specific biomarkers
Summary
Epithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge. These subtypes are very different entities carrying distinct genetic risk factors, molecular signatures, prognoses and responses to treatment [3, 4] They are supposed to arise from distinct anatomical structures, such as the fimbria or mesothelium for high-grade serous cancers (HGSC) [3, 5], while the origin of both endometrioid and clear-cell EOCs is supposed to be endometrial tissue, passing through the fallopian tube and resulting in endometriosis [3]. Advanced EOC patients frequently respond to initial platinum-based chemotherapy, but the majority of them develop platinum-resistant recurrence within 18 months from the end of the upfront therapy and are candidates for second-line treatment [2]. Its efficacy has been evaluated in a subset of recurrent platinum-sensitive nonserous EOC that display defects in the homologousrecombination (HR) pathway of DNA repair [9]
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