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

Bastian Czogalla; Maja Kahaly; Doris Mayr; Elisa Schmoeckel; Beate Niesler; Anna Hester; Christine Zeder-Göß; Thomas Kolben; Alexander Burges; Sven Mahner; Udo Jeschke; Fabian Trillsch

doi:10.2147/CMAR.S210004

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

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

Affiliations

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.