Abstract
Simple SummaryHigh grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer without effective therapeutic options. The high prevalence of mutations (~96%) in tumor suppressor p53 is a hallmark of HGSOC. Estrogen receptor-beta (ERβ) has been reported to be another important player in HGSOC, although the pro-versus anti-tumorigenic role of its different isoforms remains unclear. The aim of this study was to analyze the crosstalk between ERβ and mutant p53 and its impact on the pro-tumorigenic processes in HGSOC. Using the HGSOC cell line models and patient tumor tissue specimens, we demonstrated functional interaction between the ERβ2 isoform and mutant p53 and their ability to co-dependently increase FOXM1 gene transcription, decrease cell death, increase cell proliferation, and mediate resistance to carboplatin treatment. Furthermore, high levels of ERβ2 as well as FOXM1 correlated with worse patient survival. Collectively, our data suggest that the ERβ2-mutant p53-FOXM1 axis could be a novel therapeutic target for HGSOC.High grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of epithelial ovarian cancer. Prevalence (~96%) of mutant p53 is a hallmark of HGSOC. Estrogen receptor-beta (ERβ) has been reported to be another important player in HGSOC, although the pro-versus anti-tumorigenic role of its different isoforms remains unsettled. However, whether there is functional interaction between ERβ and mutant p53 in HGSOC is unknown. ERβ1 and ERβ2 mRNA and protein analysis in HGSOC cell lines demonstrated that ERβ2 is the predominant isoform in HGSOC. Specificity of ERβ2 antibody was ascertained using cells depleted of ERβ2 and ERβ1 separately with isoform-specific siRNAs. ERβ2-mutant p53 interaction in cell lines was confirmed by co-immunoprecipitation and in situ proximity ligation assay (PLA). Expression levels of ERβ2, ERα, p53, and FOXM1 proteins and ERβ2-mutant p53 interaction in patient tumors were determined by immunohistochemistry (IHC) and PLA, respectively. ERβ2 levels correlate positively with FOXM1 levels and negatively with progression-free survival (PFS) and overall survival (OS). Quantitative chromatin immunoprecipitation (qChIP) and mRNA expression analysis revealed that ERβ2 and mutant p53 co-dependently regulated FOXM1 gene transcription. The combination of ERβ2-specific siRNA and PRIMA-1MET that converts mutant p53 to wild type conformation increased apoptosis. Our work provides the first evidence for a novel ERβ2-mutant p53-FOXM1 axis that can be exploited for new therapeutic strategies against HGSOC.
Highlights
Epithelial ovarian cancer (EOC) is a leading cause of fatality among gynecological cancers [1]
Levels of the ERβ2 mRNA was higher than ERβ1 mRNA levels in the High grade serous ovarian cancer (HGSOC) cells, but there was no significant difference in the isoform mRNA expression in FT282-c11 cells (Figure 1A)
ERβ2 protein levels were higher than ERβ1 levels in the HGSOC cell as compared to the levels in the untransformed FT282-c11 cells
Summary
Epithelial ovarian cancer (EOC) is a leading cause of fatality among gynecological cancers [1]. It represents a group of complex and heterogeneous diseases of which highgrade serous ovarian cancer (HGSOC) is the most aggressive and accounts for more than. 60% of EOCs and over 70% of all deaths due to ovarian cancer [2]. HGSOC is commonly diagnosed at an advanced stage [3]. Recent studies have indicated that HGSOC may have dual origins from both fallopian tube and ovarian surface epithelium [4,5]. HGSOCs are typically high-grade, genetically unstable, and harbor p53 (TP53) mutations [2,6]. While wild type p53 is expressed in low-grade serous carcinomas (LGSOC), mutant or null alleles of p53 are universally (~96%) present in HGSOC [2].
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