NRF2 drives an oxidative stress response predictive of breast cancer
Wolowczyk, Camilla; Neckmann, Ulrike; Aure, Miriam Ragle; Hall, Martina; Johannessen, Bjarne; Zhao, Sen; Skotheim, Rolf I.; Andersen, Sonja Benedikte; Zwiggelaar, Rosalie Theda Margien; Steigedal, Tonje S.; Lingjærde, Ole Christian; Sahlberg, Kristine Kleivi; Almaas, Eivind; Bjørkøy, Geir
Peer reviewed, Journal article
Published version
Date
2022Metadata
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Original version
Free Radical Biology & Medicine. 2022, 184 170-184. 10.1016/j.freeradbiomed.2022.03.029Abstract
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.