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. 2021 Feb 19:12:564002.
doi: 10.3389/fendo.2021.564002. eCollection 2021.

G Protein-Coupled Estrogen Receptor Correlates With Dkk2 Expression and Has Prognostic Impact in Ovarian Cancer Patients

Patricia Fraungruber  1 , Till Kaltofen  1 , Sabine Heublein  1   2 , Christina Kuhn  1 , Doris Mayr  3 , Alexander Burges  1 , Sven Mahner  1 , Philipp Rathert  4 , Udo Jeschke  1   5 , Fabian Trillsch  1
Affiliations

G Protein-Coupled Estrogen Receptor Correlates With Dkk2 Expression and Has Prognostic Impact in Ovarian Cancer Patients

Patricia Fraungruber et al. Front Endocrinol (Lausanne). .

Abstract

Purpose: Wnt 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.

Methods: Expression 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.

Results: Highest 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).

Conclusion: Dkk2 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.

Keywords: Dickkopf 2; G protein-coupled estrogen receptor; Wnt signaling; epithelial ovarian cancer; estrogen.

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Conflict of interest statement

SM received research support, advisory board, honoraria and travel expenses from AstraZeneca, Clovis, Medac, MSD, PharmaMar, Roche, Sensor Kinesis, Tesaro, and Teva. FT declares research support, advisory board, honoraria and travel expenses from AstraZeneca, Medac, PharmaMar, Roche, and Tesaro. SH reports grants from Baden-Württemberg Ministry of Science, Research and the Arts, from StuRa Ruprecht-Karls-University of Heidelberg, FöFoLe LMU Munich Medical Faculty, grants from FERRING, personal fees from Roche, other from Astra Zeneca, grants from Novartis Oncology, grants and non-financial support from Apceth GmbH, non-financial support from Addex and grants from Heuer Stiftung. She further reports grants from Deutsche Forschungsgemeinschaft within the funding program Open Access Publishing, by the Baden-Württemberg Ministry of Science, Research and the Arts and by Ruprecht-Karls-University Heidelberg, outside the submitted work. TK receives a grant from the Friedrich-Baur-Stiftung. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Dkk2 expression patterns in different histological subtypes of EOC after immunohistochemical staining was performed as shown in a Kruskal-Wallis analysis for histological subtypes (A). Clear cell carcinomas (B) presented the strongest staining patterns. Low-grade serous carcinomas (LGSC; C) had shown moderate Dkk2 expression. For endometrioid (D), mucinous (E) and high-grade serous carcinomas (HGSC; F) the median IRS was lower. Scale bares equal 200 μm.
Figure 2
Figure 2
Kruskal-Wallis analysis for correlation of Dkk2 and GPER expression (A). High expression of Dkk2 (B) correlates with high GPER expression (C) in tissue samples of the same patient. Scale bares equal 200 μm.
Figure 3
Figure 3
Kaplan-Meier estimates of Dkk2 (A) and Dkk2 combined with GPER expression (B) were analyzed. Though not statistically significant, high cytoplasmic Dkk2 (A) and GPER (36) expression was connoted with a longer OS. Patients with carcinomas highly expressing both Dkk2 and GPER in the cytoplasm compared to patients with carcinomas lowly expressing Dkk2 and GPER showed significantly (61 months vs. 33 months, p=0.024) increased OS (B).
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References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin (2019) 69: (1):7–34. 10.3322/caac.21551 - DOI - PubMed
    1. Baldwin LA, Huang B, Miller RW, Tucker T, Goodrich ST, Podzielinski I, et al. . Ten-year relative survival for epithelial ovarian cancer. Obstet Gynecol (2012) 120(3):612–8. 10.1097/AOG.0b013e318264f794 - DOI - PubMed
    1. Kim JY, Cho CH, Song HS. Targeted therapy of ovarian cancer including immune check point inhibitor. Korean J Intern Med (2017) 32(5):798–804. 10.3904/kjim.2017.008 - DOI - PMC - PubMed
    1. du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer (2009) 115(6):1234–44. 10.1002/cncr.24149 - DOI - PubMed
    1. Aletti GD, Gostout BS, Podratz KC, Cliby WA. Ovarian cancer surgical resectability: relative impact of disease, patient status, and surgeon. Gynecol Oncol (2006) 100(1):33–7. 10.1016/j.ygyno.2005.07.123 - DOI - PubMed

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