Reduced mRNA expression levels of NFE2L2 are associated with poor outcome in breast cancer patients

BACKGROUND: The transcription factor nuclear factor erythroid 2-related factor 2 (NFE2L2; previously known as NRF2) is a crucial regulator of the intracellular antioxidant response. It controls the expression of genes involved in the detoxification and elimination of reactive oxidants and electrophilic agents. The role of NFE2L2 in cancer is subject of controversial discussion, as it has been reported to have both pro-and anti-tumourigenic functions. To shed some light on this paradox, we analysed the NFE2L2 mRNA expression levels in breast cancer and its association with clinicopathological features and survival. METHODS: We retrospectively evaluated the NFE2L2 mRNA expression levels in tumour tissue of two independent breast cancer patient cohorts. In the training set we analysed data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). In the test set we measured the NFE2L2 mRNA expression levels in 176 breast tumour tissues by quantitative real-time reverse transcription PCR (qRT-PCR). Group differences were analysed using Mann–Whitney U-test, and associations between NFE2L2 mRNA expression levels and clinicopathological features were examined by means of univariate and multivariate survival analyses. Furthermore, we compared NFE2L2 mRNA expression levels between tumour and normal breast tissue samples by means of 108 paired samples from the The Cancer Genome Atlas (TCGA) dataset. RESULTS: In the training set we identified an independent predictive value for high NFE2L2 mRNA expression levels [HR(disease specific death) 0.8 (0.6–1.0), P = 0.041; HR(death) 0.8 (0.6–1.0), P = 0.023] especially in the subgroup of oestrogen receptor (ER) positive tumours [HR(disease specific death) 0.6 (0.4–0.9), P = 0.008; HR(death) 0.6 (0.4–0.8), P = 0.001]. Similarly, we found this association also in the test set [HR(relapse) 0.4 (0.2–0.9), P = 0.031] and again, more pronounced in patients with ER positive tumours [HR(relapse) 0.2 (0.1–0.7), P = 0.012]. In addition, we observed generally lower NFE2L2 expression levels in tumour tissues than in normal breast tissues. CONCLUSION: We concluded that reduced NFE2L2 mRNA expression in tumour tissues is an independent predictor of shortened survival in breast cancer patients.