Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology
Received 26 March 2019
Accepted for publication 27 June 2019
Published 14 August 2019 Volume 2019:11 Pages 7673—7684
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Xueqiong Zhu
Bastian Czogalla,1 Maja Kahaly,1 Doris Mayr,2 Elisa Schmoeckel,2 Beate Niesler,3 Anna Hester,1 Christine Zeder-Göß,1 Thomas Kolben,1 Alexander Burges,1 Sven Mahner,1 Udo Jeschke,1 Fabian Trillsch1
1Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany; 2Faculty of Medicine, Institute of Pathology, Lmu Munich, Munich, Germany; 3Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
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: nuclear factor erythroid 2-related factor 2, progesterone receptor, ovarian cancer, immunohistochemistry
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]