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. 2023 Sep;149(11):8719-8728.
doi: 10.1007/s00432-023-04708-z. Epub 2023 May 2.

Nuclear receptor co-repressor NCOR2 and its relation to GPER with prognostic impact in ovarian cancer

Juliane Reichenbach  1 , Patricia Fraungruber  1 , Doris Mayr  2 , Christina Buschmann  1 , Fabian B T Kraus  1 , Nicole Elisabeth Topalov  1 , Anca Chelariu-Raicu  1 , Thomas Kolben  1 , Alexander Burges  1 , Sven Mahner  1 , Mirjana Kessler  1 , Udo Jeschke  3 , Bastian Czogalla  1 , Fabian Trillsch  4
Affiliations

Nuclear receptor co-repressor NCOR2 and its relation to GPER with prognostic impact in ovarian cancer

Juliane Reichenbach et al. J Cancer Res Clin Oncol. 2023 Sep.

Abstract

Purpose: The significance of the non-classical G-protein-coupled estrogen receptor (GPER) as positive or negative prognostic factor for ovarian cancer patients remains still controversial. Recent results indicate that an imbalance of both co-factors and co-repressors of nuclear receptors regulates ovarian carcinogenesis by altering the transcriptional activity through chromatin remodeling. The present study aims to investigate whether the expression of the nuclear co-repressor NCOR2 plays a role in GPER signaling which thereby could positively impact overall survival rates of ovarian cancer patients.

Methods: NCOR2 expression was evaluated by immunohistochemistry in a cohort of 156 epithelial ovarian cancer (EOC) tumor samples and correlated with GPER expression. The correlation and differences in clinical and histopathological variables as well as their effect on prognosis were analyzed by Spearman's correlation, Kruskal-Wallis test and Kaplan-Meier estimates.

Results: Histologic subtypes were associated with different NCOR2 expression patterns. More specifically, serous and mucinous EOC demonstrated a higher NCOR2 expression (P = 0.008). In addition, high nuclear NCOR2 expression correlated significantly with high GPER expression (cc = 0.245, P = 0.008). A combined evaluation of both high NCOR2 (IRS > 6) and high GPER (IRS > 8) expression revealed an association of a significantly improved overall survival (median OS 50.9 versus 105.1 months, P = 0.048).

Conclusion: Our results support the hypothesis that nuclear co-repressors such as NCOR2 may influence the transcription of target genes in EOC such as GPER. Understanding the role of nuclear co-repressors on signaling pathways will allow a better understanding of the factors involved in prognosis and clinical outcome of EOC patients.

Keywords: Chromatin remodeling; Epigenetic regulation; G-protein-coupled estrogen receptor; Immunohistochemistry; Nuclear co-repressor 2; Ovarian cancer.

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Conflict of interest statement

S.M. received research support, advisory board, honoraria and travel expenses from AstraZeneca, Clovis, Medac, MSD, PharmaMar, Roche, Sensor Kinesis, GSK/Tesaro, and Teva. F.T. declares research support, advisory board, honoraria and travel expenses from AstraZeneca, Eisai, Clovis, ImmunoGen, Medac, MSD, PharmaMar, Roche, and GSK/Tesaro,. 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

Fig. 1
Fig. 1
Detection of NCOR2 with immunohistochemistry. Nuclear NCOR2 staining in the subtypes serous (A), mucinous (B), endometrioid (C) and clear cell (D)
Fig. 2
Fig. 2
Boxplot graphs for NCOR2 IR-scores of the respective subtypes. Significantly different median IR-scores were found for the histological subtypes, respectively (P = 0.008), A for serous, clear cell, endometrioid and mucinous EOC and B for low-grade and high-grade serous EOC
Fig. 3
Fig. 3
GPER (A) and NCOR2 (B) staining in the same individual. For the same patient with serous EOC high GPER and high NCOR2 staining was detected
Fig. 4
Fig. 4
Kaplan–Meier estimates. Kaplan–Meier estimates of NCOR2 expression (A), GPER expression (B) and combined GPER and NCOR2 expression (C) were analyzed. Both NCOR2 and GPER expression were associated with prolonged overall survival (A, B), however, without statistical significance. A significant effect on overall survival was detected for the combined high GPER and NCOR2 expression (C)
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