NRF2 drives an oxidative stress response predictive of breast cancer

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

doi:10.1016/j.freeradbiomed.2022.03.029

NRF2 drives an oxidative stress response predictive of breast cancer

Free Radic Biol Med. 2022 May 1:184:170-184. doi: 10.1016/j.freeradbiomed.2022.03.029. Epub 2022 Apr 2.

Authors

Affiliations

¹ Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Biomedical Laboratory Science, Faculty of Natural Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim, Norway. Electronic address: camilla.wolowczyk@ntnu.no.
² Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Biomedical Laboratory Science, Faculty of Natural Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim, Norway.
³ Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Biotechnology and Food Science, Faculty of Natural Sciences, Norwegian University of Science and Technology, Trondheim, Norway; K.G.Jebsen Center for Genetic Epidemiology, Department of Public Health and General Practice, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Norway.
⁵ Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway; Norwegian Cancer Genomics Consortium, Oslo, Norway.
⁶ Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Biomedical Laboratory Science, Faculty of Natural Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
⁸ Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁹ Department of Computer Science, University of Oslo, Oslo, Norway.
¹⁰ Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Department of Research, Vestre Viken Hospital Trust, Drammen, Norway.

PMID: 35381325
DOI: 10.1016/j.freeradbiomed.2022.03.029

Abstract

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.

Keywords: 4T1 model; 66cl4; 67NR; NFE2L2; NQO1; Prognosis; SQSTM1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms* / pathology
Female
Humans
Mice
NF-E2-Related Factor 2* / genetics
NF-E2-Related Factor 2* / metabolism
Neoplasm Recurrence, Local
Oxidative Stress
Reactive Oxygen Species / metabolism

Substances

NF-E2-Related Factor 2
NFE2L2 protein, human
Nfe2l2 protein, mouse
Reactive Oxygen Species