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Czogalla, Bastian; Kahaly, Maja; Mayr, Doris; Schmoeckel, Elisa; Niesler, Beate; Kolben, Thomas; Burges, Alexander; Mahner, Sven; Jeschke, Udo; Trillsch, Fabian (2019): Interaction of ER and NRF2 Impacts Survival in Ovarian Cancer Patients. In: International Journal of Molecular Sciences, Vol. 20, No. 1, 112
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Nuclear factor erythroid 2-related factor 2 (NRF2) regulates cytoprotective antioxidant processes. In this study, the prognostic potential of NRF2 and its interactions with the estrogen receptor (ER) in ovarian cancer cells was investigated. NRF2 and ER protein expression in ovarian cancer tissue was analyzed as well as mRNA expression of NRF2 (NFE2L2) and ER (ESR1) in four ovarian cancer and one benign cell line. NFE2L2 silencing was carried out to evaluate a potential interplay between NRF2 and ER. Cytoplasmic NRF2 expression as inactive form had significantly higher expression in patients with low-grade histology (p = 0.03). In the serous cancer subtype, high cytoplasmic NRF2 expression (overall survival (OS), median 50.6 vs. 29.3 months;p = 0.04) and high ER expression (OS, median 74.5 vs. 27.1 months;p = 0.002) was associated with longer overall survival as well as combined expression of both inactive cytoplasmic NRF2 and ER in the whole cohort (median 74.5 vs. 37.7 months;p = 0.04). Cytoplasmic NRF2 expression showed a positive correlation with ER expression (p = 0.004). NFE2L2 was found to be highly expressed in the ovarian cancer cell lines OVCAR3, UWB1.289, and TOV112D. Compared with the benign cell line HOSEpiC, ESR1 expression was reduced in all ovary cancer cell lines (all p < 0.001). Silencing of NFE2L2 induced a higher mRNA expression of ESR1 in the NFE2L2 downregulated cancer cell lines OVCAR3 (p = 0.003) and ES2 (p < 0.001), confirming genetic interactions of NRF2 and ER. In this study, both inactive cytoplasmic NRF2 and high ER expression were demonstrated to be associated with improved survival in ovarian cancer patients. Further understanding of interactions within the estradiol-ER-NRF2 pathway could better predict the impact of endocrine therapy in ovarian cancer.