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

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. 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). NRF2 staining was different in both, the cytoplasm and nucleus between the histological subtypes ( =0.001 and =0.02, respectively). There was a significant difference in the PRA expression comparing all histological subtypes ( =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, =0.003) as well as of cytoplasmic NRF2 and PRB expression (cc=0.25, =0.003), confirmed by immunofluorescence double staining. Cytoplasmic NRF2 expression was associated with a longer OS (median 50.6 vs 32.5 months; =0.1) as it was seen for PRA expression (median 63.4 vs 33.1 months; =0.08), although not statistically significant. In addition, high PRB expression (median 80.4 vs 32.5 months; =0.04) and concurrent expression of cytoplasmic NRF2 and PRA were associated with a significantly longer OS (median 109.7 vs 30.6 months; =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; =0.009). Silencing of induced higher mRNA expression of in the cancer cell line OVCAR3 ( >0.05) confirming genetic interactions of NRF2 and PR. 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.