BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival
Open accessAbstract
Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.
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Estrogen stimulation of breast cancer cells that do not express BRCA1 and suffer from high intracellular ROS levels rescues NRF2 transcription, enhancing survival of these cancer cells.
“Interestingly, estrogen stimulation of breast cancer cells that do not express BRCA1 and, as a result, suffer from high intracellular ROS levels rescues NRF2 transcription, enhancing the survival of these cancer cells64.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [64]
The Results section, “Estrogen induces an Nrf2-dependent antioxidant response” (page unavailable), reports that estradiol increased NRF2 protein and NRF2-target gene expression in MCF7 breast cancer cells, and restored Nrf2 protein in BRCA1-deleted mammary epithelial cells. It does not show this combined effect in BRCA1-deficient breast cancer cells or demonstrate that estradiol improved their survival. It also reports no change in NRF2 mRNA in the treated MCF7 cells, so the claim is unsupported if “NRF2 transcription” means transcription of the NRF2 gene. (LLM, conf=0.88)
Experimental — accuracy not yet measuredProTα interacts with the Kelch domain of Keap1 and shuttles it into the nucleus, thereby preventing its association with Nrf2.
“ProTα interacts with the Kelch domain of Keap1 and shuttles it into the nucleus, thereby preventing its association with Nrf2 [82].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [82]
The BRCT domain of BRCA1 interacts with the ETGE motif in the Neh2 domain of Nrf2, which inhibits Keap1-mediated ubiquitination and increases the response to oxidative stress.
“The BRCT domain of BRCA1 interacts with the ETGE motif in the Neh2 domain of Nrf2, which inhibits Keap1-mediated ubiquitination and increases the response to oxidative stress [82,83].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [82]
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- Authors
- Gorrini, C., Baniasadi, P. S., Harris, I. S., Silvester, J., Inoue, S., Snow, B., Joshi, P. A., Wakeham, A., Molyneux, S. D., Martin, B., Bouwman, P., Cescon, D. W., Elia, A. J., Winterton-Perks, Z., Cruickshank, J., Brenner, D., Tseng, A., Musgrave, M., Berman, H. K., Khokha, R., Jonkers, J., Mak, T. W., & Gauthier, M. L.
- Affiliations
- University Health Network (CA)
- St. Michael's Hospital (CA)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Mak, Tak W.
- Gauthier, Mona L.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2013-07-15
- Volume
- 210
- Issue
- 8
- Pages
- 1529-1544
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3727320
- OpenAlex
- W2150140277
- Cited by
- 289
- References
- 71
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 19 · 2023: 23 · 2022: 28 · 2021: 31 · 2020: 26 · 2019: 37 · 2018: 19 · 2017: 14 · 2016: 24 · 2015: 22 · 2014: 19 · 2013: 4
- FWCI
- 10.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by-sa)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Ohio State University
- Ottawa Hospital Research Institute
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- BRCA1, Nrf2, antioxidant signaling, oxidative stress, reactive oxygen species, protein-protein interaction, protein stability, 53BP1, mammary epithelial cells, estrogen, tumor suppression, cell survival
- MeSH terms
- Animals, Antioxidants, Breast Neoplasms, Cell Line, Cell Survival, Cell Transformation, Neoplastic, Epithelial Cells, Estrogens, Female, Humans, Mammary Glands, Animal, Mutation, Protein Binding, Signal Transduction, Gene Expression Regulation, Neoplastic, NAD(P)H Dehydrogenase (Quinone), Reactive Oxygen Species, Oxidative Stress, BRCA1 Protein, NF-E2-Related Factor 2, Mice, Ubiquitination, Protein Stability, Gene Knockout Techniques
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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