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Cancer Manag Res. 2019 Aug 14;11:7673-7684. doi: 10.2147/CMAR.S210004. eCollection 2019.

Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology.

Author information

1
Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany.
2
Faculty of Medicine, Institute of Pathology, Lmu Munich, Munich, Germany.
3
Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.

Abstract

Purpose:

This study aimed to investigate the potential prognostic impact of nuclear factor erythroid 2-related factor 2 (NRF2) and progesterone receptor A (PRA)/progesterone receptor B (PRB) in ovarian cancer patients which might be the rationale for putative new treatment strategies.

Patients and methods:

The presence of NRF2 and PRA/PRB was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC). Staining of NRF2 and PRA/PRB was rated using the semi-quantitative immunoreactive score (IR score, Remmele's score) and correlated to clinical and pathological data. NRF2 and PRA/PRB expression were compared with respect to the overall survival (OS).

Results:

NRF2 staining was different in both, the cytoplasm and nucleus between the histological subtypes (p=0.001 and p=0.02, respectively). There was a significant difference in the PRA expression comparing all histological subtypes (p=0.02). Histological subtypes showed no significant differences in the PRB expression. A strong correlation of cytoplasmic NRF2 and PRA expression was detected (cc=0.247, p=0.003) as well as of cytoplasmic NRF2 and PRB expression (cc=0.25, p=0.003), confirmed by immunofluorescence double staining. Cytoplasmic NRF2 expression was associated with a longer OS (median 50.6 vs 32.5 months; p=0.1) as it was seen for PRA expression (median 63.4 vs 33.1 months; p=0.08), although not statistically significant. In addition, high PRB expression (median 80.4 vs 32.5 months; p=0.04) and concurrent expression of cytoplasmic NRF2 and PRA were associated with a significantly longer OS (median 109.7 vs 30.6 months; p=0.02). The same relationship was also noted for NRF2 and PRB with improved OS for patients expressing both cytoplasmic NRF2 and PRB (median 153.5 vs 30.6 months; p=0.009). Silencing of NFE2L2 induced higher mRNA expression of PGR in the cancer cell line OVCAR3 (p>0.05) confirming genetic interactions of NRF2 and PR.

Conclusion:

In this study, the combination of cytoplasmic NRF2 and high PRA/PRB expression was demonstrated to be associated with improved overall survival in ovarian cancer patients. Further understanding of interactions within the NRF2/AKR1C1/PR pathway could open new additional therapeutic approaches.

KEYWORDS:

immunohistochemistry; nuclear factor erythroid 2-related factor 2; ovarian cancer; progesterone receptor

Conflict of interest statement

Bastian Czogalla has received a research grant from the “Monika Kutzner” foundation and “Brigitte & Dr. Konstanze Wegener” foundation. Anna Hester has received a research grant from the “Walter Schulz” foundation and advisory board, speech honoraria and travel expenses from Roche and Pfizer. Thomas Kolben´s relative is employed at Roche AG. Research support, advisory board, honoraria, and travel expenses from AstraZeneca, Clovis, Medac, MSD, Novartis, PharmaMar, Roche, Sensor Kinesis, Tesaro, Teva have been received by Sven Mahner and from AstraZeneca, Medac, PharmaMar, Roche, Tesaro by Fabian Trillsch. All authors report no other conflicts of interest in this work.

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