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NRF2 drives an oxidative stress response predictive of breast cancer

2022; Elsevier BV; Volume: 184; Linguagem: Inglês

10.1016/j.freeradbiomed.2022.03.029

1873-4596

Camilla Wolowczyk, Ulrike Neckmann, Miriam R. R. Aure, Martina Hall, Bjarne Johannessen, Sen Zhao, Rolf I. Skotheim, Sonja Andersen, Rosalie T. Zwiggelaar, Tonje S. Steigedal, Ole Christian Lingjærde, Kristine Kleivi Sahlberg, Eivind Almaas, Geir Bjørkøy,

Cancer-related molecular mechanisms research

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.