NRF2 drives an oxidative stress response predictive of breast cancer

Many breast cancer patients are diagnosed with small, well-differentiated, hormone receptor-positive tumors. Risk of relapse is not easily identified in these patients, resulting in overtreatment. To identify metastasis-related gene expression patterns, we compared the transcriptomes of the non-metastatic 67NR and metastatic 66cl4 cell lines from the murine 4T1 mammary tumor model. The transcription factor nuclear factor, erythroid 2-like 2 (NRF2, encoded by NFE2L2) was constitutively activated in the metastatic cells and tumors, and correspondingly a subset of established NRF2-regulated genes was also upregulated. Depletion of NRF2 increased basal levels of reactive oxygen species (ROS) and severely reduced ability to form primary tumors and lung metastases. Consistently, a set of NRF2-controlled genes was elevated in breast cancer biopsies. Sixteen of these were combined into a gene expression signature that significantly improves the PAM50 ROR score, and is an independent, strong predictor of prognosis, even in hormone receptor-positive tumors. [Display omitted] •Constitutive NRF2 activation in metastatic cells shows reduced basal ROS levels and impaired ability to cope with additional oxidative stress.•NRF2 knockdown causes a clear increase in basal ROS and restored energy production via oxidative phosphorylation.•NRF2 depletion in metastatic cancer cells impairs primary tumor development and formation of lung metastases.•A 16-gene signature of NRF2-related genes is a strong and independent prognostic predictor of breast cancer.