Abstract
PurposeWnt pathway modulator Dickkopf 2 (Dkk2) and signaling of the G protein-coupled estrogen receptor (GPER) seem to have essential functions in numerous cancer types. For epithelial ovarian cancer (EOC), it has not been proven if either Dkk2 or the GPER on its own have an independent impact on overall survival (OS). So far, the correlation of both factors and their clinical significance has not systematically been investigated before.MethodsExpression levels of Dkk2 were immunohistochemically analyzed in 156 patient samples from different histologic subtypes of EOC applying the immune-reactivity score (IRS). Expression analyses were correlated with clinical and pathological parameters to assess for prognostic relevance. Data analysis was performed using Spearman’s correlations, Kruskal-Wallis-test and Kaplan-Meier estimates.ResultsHighest Dkk2 expression of all subtypes was observed in clear cell carcinoma. In addition, Dkk2 expression differed significantly (p<0.001) between low and high grade serous ovarian cancer. A significant correlation of Dkk2 with the cytoplasmic GPER expression was noted (p=0.001) but not for the nuclear estrogen receptor alpha (ERα) or beta (ERβ). Patients exhibiting both, high expression Dkk2 (IRS>4) and GPER (IRS>8), had a significantly better overall survival compared to patients with low expression (61 months vs. 33 months; p=0.024).ConclusionDkk2 and GPER expression correlates in EOC and combined expression of both is associated with improved OS. These findings underline the clinical significance of both pathways and indicate a possible prognostic impact as well as a potential for treatment strategies addressing interactions between estrogen and Wnt signaling in ovarian cancer.
Highlights
Epithelial ovarian cancer (EOC) causes most deaths of gynecological malignancies [1] with a relative 5-year survival of almost 45% [2]
Dkk2 seems able to act as agonist as well as antagonist for Wnt/low-density-lipoprotein-related protein 6 (LRP6) signaling depending on the cellular context and cofactors such as krm2 [18,19,20]
While endometrioid and mucinous EOCs exhibited both a median immunereactivity score (IRS) of 4, the overall cohort of serous EOCs had moderate staining extent at IRS of 6 which subdivided into high-grade serous histology with an IRS of 4 and significantly higher for low-grade serous histology with an IRS of 6
Summary
Epithelial ovarian cancer (EOC) causes most deaths of gynecological malignancies [1] with a relative 5-year survival of almost 45% [2]. Apart from clinicopathological aspects such as the stage in the system of the International Federation of Gynecology and Obstetrics (FIGO), volume of residual disease after debulking surgery, patients’ age, and histological subtype [4,5,6,7], there are no reliable prognostic factors to predict the clinical course. Secreted Wnt glycoproteins translate their function via binding to Frizzled receptors and co-receptors such as low-density-lipoprotein-related protein 5/6 (LRP5/6) [11]. Dkk seems able to act as agonist as well as antagonist for Wnt/LRP6 signaling depending on the cellular context and cofactors such as krm2 [18,19,20]. In EOC Zhu et al suggest that Dkk may functions as a Wnt pathway inhibitor [13]
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