High Expression of NRF2 and Low Expression of KEAP1 Predict Worse Survival in Patients With Operable Triple-Negative Breast Cancer

Sep 24, 2026

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Triple-negative breast cancer (TNBC) remains difficult to treat, with limited effective therapeutic options. This study evaluates how nuclear factor erythroid 2-related factor 2 (NRF2) and its inhibitor Kelch-like ECH-associated protein 1 (KEAP1) are expressed in operable TNBC and how these markers relate to patient outcomes. Tissue microarrays from 203 surgically treated TNBC cases were assessed by immunohistochemistry, and findings were validated using 225 samples from the METABRIC dataset.

LanguageEnglish

CategoryHealthcare

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Pages18

Reading Time45 min

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Abstract

Purpose

Methods

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J Breast Cancer. 2023 Oct;26(5):461-478 [https://doi.org/10.4048/jbc.2023.26.e42](https://doi.org/10.4048/jbc.2023.26.e42)[ ](https://doi.org/10.4048/jbc.2023.26.e42)pISSN 1738-6756·eISSN 2092-9900 Original Article Received: Feb 15, 2023 Revised: Jul 4, 2023 Accepted: Aug 10, 2023 Published online: Sep 19, 2023 Correspondence to Ahwon Lee Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. Email: [klee@catholic.ac.kr](klee@catholic.ac.kr) Data generated as part of this report was presented at the 2022 International Congress of Asian Oncology Society, June 16–18, 2022. © 2023 Korean Breast Cancer Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ([https://](https://)[ ](https://)[creativecommons.org/licenses/by-nc/4.0/](creativecommons.org/licenses/by-nc/4.0/)) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ORCID iDs Young Sub Lee [https://orcid.org/0000-0003-0841-1122](https://orcid.org/0000-0003-0841-1122)[ ](https://orcid.org/0000-0003-0841-1122)Jun Kang [https://orcid.org/0000-0002-7967-0917](https://orcid.org/0000-0002-7967-0917)[ ](https://orcid.org/0000-0002-7967-0917)Eun Sun Jung [https://orcid.org/0000-0002-8451-939X](https://orcid.org/0000-0002-8451-939X)Ahwon Lee [https://orcid.org/0000-0002-2523-9531](https://orcid.org/0000-0002-2523-9531) High Expression of NRF2 and Low Expression of KEAP1 Predict Worse Survival in Patients With Operable Triple-Negative Breast Cancer Young Sub Lee 1, Jun Kang 2, Eun Sun Jung 1, Ahwon Lee 2 1Department of Hospital Pathology, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea 2Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea ABSTRACT Purpose: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer. Currently, no effective treatment options for this condition exist. Nuclear factor erythroid 2-related factor 2 (NRF2), encoded by nuclear factor erythroid-derived 2-like 2 (NFE2L2) gene and its endogenous inhibitor, Kelch-like ECH-associated protein 1 (KEAP1), both participate in cellular defense mechanisms against oxidative stress and contribute to chemoresistance and tumor progression in numerous types of cancers. This study aimed to evaluate the expression patterns of NRF2 and KEAP1 and their prognostic value in operable TNBC. Methods: Tissue microarrays were prepared using tumor tissues collected from 203 patients with TNBC who underwent surgery. Immunohistochemical staining analyses of NRF2 and KEAP1 were performed. The expression of each immunomarker was categorized into two groups (low or high) based on the median H-score. We analyzed the association between the expression of each immunomarker and clinicopathological information to predict survival. A total of 225 TNBC samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were used to validate our results. Results: NRF2 immunoreactivity was detected in the nucleus and was associated with histologic grade and Ki-67 index, whereas KEAP1 immunoreactivity was detected in the cytoplasm and was associated with the Ki-67 index. Survival analyses showed that NRF2 and KEAP1 expressions were independent prognostic factors for overall survival (OS) (hazard ratio [HR], 2.45 and 0.30; p= 0.015 and 0.016, respectively) and disease-free survival (HR, 2.27 and 0.42; p= 0.019 and 0.022, respectively) . NFE2L2 mRNA expression was an independent prognostic factor for OS (HR, 0.59; p= 0.009) in the METABRIC dataset. Conclusion: High NRF2 and low KEAP1 expressions independently predicted poor survival in patients with operable TNBC. Furthe

FAQs

What is the purpose of evaluating NRF2 and KEAP1 in operable triple-negative breast cancer?

To assess expression patterns of NRF2 and KEAP1 and determine their prognostic value for patient survival in operable TNBC.

How were NRF2 and KEAP1 expression levels measured and categorized?

NRF2 and KEAP1 were assessed by immunohistochemical staining on tissue microarrays, and expression was classified into low or high groups based on the median H-score.

What survival outcomes are associated with high NRF2 and low KEAP1 expression?

High NRF2 and low KEAP1 independently predicted worse overall survival and disease-free survival, and NFE2L2 mRNA expression also independently predicted overall survival in the METABRIC dataset.

Sep 24, 2026

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