Genetic Polymorphisms and Protein Expression of NRF2 and Sulfiredoxin Predict Survival Outcomes in Breast Cancer
Published version of a preprint
Abstract
NRF2 activates several protective genes, such as sulfiredoxin (SRXN1), as a response to oxidative and xenobiotic stress. Defects in NRF2 pathway may increase cancer susceptibility. In tumor cells, activation of NRF2 may lead to chemo- and radioresistance and thus affect patient outcome. Nine single-nucleotide polymorphisms on NRF2 gene and eight on SRXN1 were genotyped in 452 patients with breast cancer and 370 controls. Protein expression of NRF2 and SRXN1 was studied in 373 breast carcinomas by immunohistochemistry. Statistical significance of the associations between genotypes, protein expression, clinicopathologic variables, and survival was assessed. A high level (>25%) of cytoplasmic NRF2 positivity was observed in 237 of 361 (66%) and SRXN1 positivity was observed in 82 of 363 (23%) cases. The NRF2 rs6721961 genotype TT was associated with increased risk of breast cancer [P = 0.008; OR, 4.656; confidence interval (CI), 1.350-16.063] and the T allele was associated with a low extent of NRF2 protein expression (P = 0.0003; OR, 2.420; CI, 1.491-3.926) and negative SRXN1 expression (P = 0.047; OR, 1.867; CI = 1.002-3.478). The NRF2 rs2886162 allele A was associated with low NRF2 expression (P = 0.011; OR, 1.988; CI, 1.162-3.400) and the AA genotype was associated with a worse survival (P = 0.032; HR, 1.687; CI, 1.047-2.748). The NRF2 rs1962142 T allele was associated with a low level of cytoplasmic NRF2 expression (P = 0.036) and negative sulfiredoxin expression (P = 0.042). The NRF2 rs2706110 AA genotype was associated with an increased risk of breast cancer, and the SRXN1 rs6053666 C allele was associated with a decrease in breast cancer risk (P = 0.011 and 0.017). NRF2 and SRXN1 genetic polymorphisms are associated with breast cancer risk and survival, implicating that mechanisms associated with reactive oxygen species and NRF2 pathway are involved in breast cancer initiation and progression.
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Aberrant Nrf2 expression and poor prognosis have been revealed in a wide range of cancers, including lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas.
“numerous studies have revealed aberrant Nrf2 expression and poor prognosis in a wide range of cancers, including, among others, lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas [161,162,169,170,171,173,174]”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [171]
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“But, the rs2706110 AA genotype was associated with an increased risk of breast cancer (Hartikainen et al., 2012).”
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“In addition, polymorphisms in NRF2 lead to poor prognosis in lung and breast cancers, etc.([131-133]).”
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“The T allele associates with a low extent of NRF2 protein expression, resulting in lower SRXN1 expression and increased risk of breast cancer [6].”
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“, underlying the complex effect of NFE2L2 gene in cancer predisposition and progression [68].”
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“Genetic polymorphism of NRF2 on several SNPs (including rs6721961 and rs2886162) were associated with breast cancer risk (Hartikainen et al., 2012).”
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“The rs6721961 T or rs1962142 T allele can also influence the positive feedback loop of transcriptional activation of NRF2 gene and decrease NRF2 protein level.(13,14) However, the frequency of the NRF2 rs6721961 was not TABLE 4 Interaction analysis of KEAP1 and NRF2 polymorphisms and risk of colorectal cancer”
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“Likewise, individuals with the Nrf2*C/C genotype had slightly increased PC risk, but it did not reach statistical significance.”
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Cytochrome b561 Serves as a Potential Prognostic Biomarker and Target for Breast Cancer
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“Meanwhile, the expression level of Srx was negatively correlated with the tumor prognosis [16].”
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“Activated NRF2 by KEAP1 is associated with an increased progression of cancer and reduced survival [9–11].”
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Sulfiredoxin‐1 is a promising novel prognostic biomarker for hepatocellular carcinoma
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“What is more, women carrying this specific genotype have higher risk for breast cancer development and decreased protein expression in cancer tissue [48].”
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“[47] Also studies have shown that the C allele of rs6053666 of SRXN1 gene was associated with a decrease in breast carcinoma.[48] Previous study done by Ramesh et al.”
ResultIron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice
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The Role of Genetic Polymorphisms in Nrf2 and P73 in Egyptian Women with Breast Cancer
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“Genetic polymorphisms of Nrf2 on several SNPs (including rs6721961) were associated with breast cancer risk (Hartikainen et al., 2012).”
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“tumor growth factor (TGF)-β, Notch and Nrf2 [19], In addition, Nrf2 polymorphisms could be involved in control of Srx levels and its role in malignant induction [20].”
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“6 times (452 cases and 370 controls) [34].”
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Somatic Mutations in KEAP1-NRF2 Complex in Breast Cancer
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“Relative to NRF2 -selected polymorphisms, women with a homozygous (AA) genotype of rs6721961 had an increased risk of breast cancer development [16].”
BackgroundResultInfluentialNrf2 Contributes to the Poor Prognosis and Chemoresistance
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“The Nrf2 polymorphism contributes to poor prognosis in cancers, including cholangiocarcinoma [65], lung cancer [66], and breast cancer [67].”
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“The results of some studies indicate that the presence of rs6721961 T allele (TT genotype) and rs2706110 AA genotype increases the risk of breast cancer [75].”
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Sulfiredoxin Promotes Cancer Cell Invasion through Regulation of the miR143-Fascin Axis
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Targeting Nrf2 in inflammation and cancer
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NRF2 AND P73 POLYMORPHISMS IN EGYPTIAN WOMEN WITH BREAST CANCER
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“Keap1 is essential for the regulation of Nrf2 activity; both of them enhanced proliferation, drug resistance and could be potent survival factors in cancers [88].”
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“Correction Correction: Genetic Polymorphisms and Protein Expression of NRF2 and Sulfiredoxin Predict Survival Outcomes in Breast Cancer In this article (Cancer Res 2012;72:5537–46), which was published in theNovember 1, 2012, issue of Cancer Research (1), in the last paragraph of the Results section, the sentence ". .…”
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“Sulfiredoxin (SRXN1) was previously found to be associated with cerebrovascular disease in a Finnish cohort [41], and SRXN1 genetic polymorphisms were associated with breast cancer risk and survival [42].”
BackgroundNRF-2 and KEAP-1 Expression in Pancreatic Cancer Patients: A clinicopathological study
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“This provides a regulated antioxidant response, detoxification, and cancer prevention (Hartikainen et al., 2012).”
BackgroundAssociation Between Polymorphisms of NRF2 and Breast Cancer Risk in Japanese Population
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“63,64 The SNPs(−650 C/A, −617 C/A) located in the promoter region of the Nrf2 gene have been significantly linked to acute lung injury, exacerbated COPD, and an increased likelihood of respiratory failure within a restricted demographic.”
Choi, H. Y., Kwon, H., & Hah, Y. (2026) · Antioxidants · doi:10.3390/antiox15101223
- Authors
- Hartikainen, J. M., Tengström, M., Kosma, V.-M., Kinnula, V. L., Mannermaa, A., & Soini, Y.
- Affiliations
- University of Helsinki (FI)
- Corresponding author
- Hartikainen, Jaana M.
- Venue
- Cancer Research
- Published
- 2012-10-31
- Volume
- 72
- Issue
- 21
- Pages
- 5537-5546
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2169747445
- Cited by
- 89
- References
- 44
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 7 · 2019: 8 · 2017: 6 · 2016: 12 · 2015: 9 · 2014: 8 · 2013: 5
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- Nrf2, sulfiredoxin, SRXN1, breast cancer, single nucleotide polymorphisms, genetic polymorphism, protein expression, survival outcomes, oxidative stress, xenobiotic stress
- MeSH terms
- Breast Neoplasms, Female, Genotype, Humans, Immunohistochemistry, Proportional Hazards Models, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Tissue Array Analysis, Oxidoreductases Acting on Sulfur Group Donors, NF-E2-Related Factor 2, Kaplan-Meier Estimate, Transcriptome
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