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 Inge; Andersen, Sonja; Zwiggelaar, Rosalie T.; Steigedal, Tonje S.; Lingjærde, Ole Christian; Sahlberg, Kristine Kleivi; Almaas, Eivind; Bjørkøy, Geir

doi:10.1016/j.freeradbiomed.2022.03.029

Cited by 11 publications

(6 citation statements)

References 46 publications

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“…Our data is supported by previous reports showing that disruption of the micronuclear envelope exposes self-DNA to the cytosol, followed by recruitment of cGAS and activation of cGAS-STING signaling [38,57]. Our observation of mtDNA leakage is supported by our previous findings that show dysfunctional mitochondrial in metastatic cancer cells, characterized by high mtROS production, hyperpolarized mitochondria with higher proton leak, and lower respiratory capacity [58]. We therefore speculate that elevated levels of mitochondrial components and hyperpolarized mitochondria could be a compensatory mechanism to increase ATP production, but also result in mitochondrial damage and mtDNA release in the cytosol.…”

Section: Discussionsupporting

confidence: 92%

Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

et al. 2023

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Background To our current understanding, solid tumors depend on suppressed local immune reactions, often elicited by the interaction between tumor cells and tumor microenvironment (TME) components. Despite an improved understanding of anti-cancer immune responses in the TME, it is still unclear how immuno-suppressive TME are formed and how some cancer cells survive and metastasize. Methods To identify the major adaptations that cancer cells undergo during tumor development and progression, we compared the transcriptome and proteome from metastatic 66cl4 and non-metastatic 67NR cell lines in culture versus their corresponding mouse mammary primary tumors. Using confocal microscopy, RT-qPCR, flow cytometry and western blotting, we studied the signaling pathway and the mechanisms involved. In addition, we used public gene expression data from human breast cancer biopsies to evaluate the correlation between gene expression and clinical outcomes in patients. Results We found that type I interferon (IFN-I) response was a key differentially regulated pathway between metastatic and non-metastatic cell lines and tumors. The IFN-I response was active in metastatic cancer cells in culture and markedly dampened when these cells formed primary tumors. Interestingly, the opposite was observed in non-metastatic cancer cells and tumors. Consistent with an active IFN-I response in culture, the metastatic cancer cells displayed elevated levels of cytosolic DNA from both mitochondria and ruptured micronuclei with concomitant activation of cGAS-STING signaling. Interestingly, decreased IFN-I-related gene expression in breast cancer biopsies correlated with an unfavourable prognosis in patients. Conclusion Our findings show that IFN-I response is dampened in the tumors with the metastatic ability and lower IFN-I expression predicts poor prognosis in triple-negative and HER2 enriched breast cancer patients. This study highlights the possibility of reactivating the IFN-I response as a potential therapeutic strategy in breast cancer. Graphical abstract

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Section: Discussionsupporting

confidence: 92%

Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

et al. 2023

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“…And, overexpression of NRF2 upregulated expression of G6PD in MCF‐7 and MDA‐MB‐231 cells through the elevated expression of Notch 1, which promoted the BC cell migration [114] . However, depletion of NRF2 significantly increased the basal levels of ROS in metastatic 66cl4 cell lines from the murine 4T1 mammary tumor model and reduced the formation of BC primary tumor and lung metastasis [115] . On the one hand, the antioxidants provided protection against oxidative DNA damage and E2-induced mammary carcinogenesis in part through NRF2 induction in BC [116] , [117] , [118] .…”

Section: Pentose Phosphate Pathway (Ppp)mentioning

confidence: 93%

Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets

Zheng

Wang

et al. 2022

Translational Oncology

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“…Xie et al studied a series of novel direct Keap1-Nrf2 PPI inhibitors and their role in increasing the availability of Nrf2 for antioxidant activity and attenuating estrogen-mediated responses in breast cancer [283]. It has been shown that the NRF2 gene signature can potentially be used to identify patients who are not likely to experience metastatic recurrence [284], as cancer cells experience high levels of oxidative stress during metastasis [285].…”

Section: Estrogens and Oxidative Stress In Breast Cancermentioning

confidence: 99%

Oxidative Stress in Breast Cancer: A Biochemical Map of Reactive Oxygen Species Production

Bel’skaya,

Dyachenko

2024

CIMB

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This review systematizes information about the metabolic features of breast cancer directly related to oxidative stress. It has been shown those redox changes occur at all levels and affect many regulatory systems in the human body. The features of the biochemical processes occurring in breast cancer are described, ranging from nonspecific, at first glance, and strictly biochemical to hormone-induced reactions, genetic and epigenetic regulation, which allows for a broader and deeper understanding of the principles of oncogenesis, as well as maintaining the viability of cancer cells in the mammary gland. Specific pathways of the activation of oxidative stress have been studied as a response to the overproduction of stress hormones and estrogens, and specific ways to reduce its negative impact have been described. The diversity of participants that trigger redox reactions from different sides is considered more fully: glycolytic activity in breast cancer, and the nature of consumption of amino acids and metals. The role of metals in oxidative stress is discussed in detail. They can act as both co-factors and direct participants in oxidative stress, since they are either a trigger mechanism for lipid peroxidation or capable of activating signaling pathways that affect tumorigenesis. Special attention has been paid to the genetic and epigenetic regulation of breast tumors. A complex cascade of mechanisms of epigenetic regulation is explained, which made it possible to reconsider the existing opinion about the triggers and pathways for launching the oncological process, the survival of cancer cells and their ability to localize.

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NRF2 drives an oxidative stress response predictive of breast cancer

Cited by 11 publications

References 46 publications

Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets

Oxidative Stress in Breast Cancer: A Biochemical Map of Reactive Oxygen Species Production

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