Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2020

01-02-2020 | Breast Cancer | Review

The prognostic value of NRF2 in breast cancer patients: a systematic review with meta-analysis

Authors: Micaela Almeida, Mafalda Soares, Ana Cristina Ramalhinho, José Fonseca Moutinho, Luiza Breitenfeld, Luísa Pereira

Published in: Breast Cancer Research and Treatment | Issue 3/2020

Login to get access

Abstract

Purpose

Nuclear factor E2-related factor 2 (NRF2) is a transcription factor that plays a major role in the regulation of intracellular antioxidant response. The effect of NRF2 overexpression in many malignancies is still unclear and recent meta-analysis correlated NRF2 overexpression with poor prognosis in a variety of human cancers. However, the effect of NRF2 overexpression in breast cancer is still unclear. Thus, the main goal of this work was to clarify the role of NRF2 expression in survival and relapse of breast cancer patients by performing a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement, followed by a meta-analysis.

Methods

The electronic search was conducted in PubMed, Scopus, SciELO, Web of Science and Embase between November of 2017 and September of 2018. To be included, studies should evaluate NRF2 expression in breast cancer tissue, through immunohistochemistry and/or mRNA and had to report one or more of the following outcomes: overall survival (OS), disease-free survival (DFS), mean survival and median survival.

Results

For the meta-analysis, seven studies were included and NRF2 expression was correlated with OS and DFS. It was observed that compared to patients with low NRF2 expression, patients with NRF2 overexpression had poorer OS with a hazard ratio of 1.82 (95% CI 1.32–2.50; p value < 0.0001), and poorer DFS, with a hazard ratio of 1.79 (95% CI 1.07–3.01; p value = 0.03).

Conclusions

These results suggest that tumours that overexpress NRF2 have a worse clinical outcome. Thus, NRF2 expression could be a marker for the prognostic of breast cancer patients and, in the future, it would be pertinent to focus on improving treatment efficacy for patients with NRF2 overexpression.
Literature
1.
Jaramillo MC, Zhang DD (2013) The emerging role of the Nrf2–Keap1 signaling pathway in cancer. Genes Dev 27:2179–2191CrossRef
2.
Cho H-Y, Marzec J, Kleeberger SR (2015) Functional polymorphisms in Nrf2: implications for human disease. Free Radic Biol Med 88:362–372CrossRef
3.
Jeddi F, Soozangar N, Sadeghi MR, Somi MH, Samadi N (2017) Contradictory roles of Nrf2/Keap1 signaling pathway in cancer prevention/promotion and chemoresistance. DNA Repair 54:13–21CrossRef
4.
Guo Y, Yu S, Zhang C, Kong A-NT (2015) Epigenetic regulation of Keap1-Nrf2 signaling. Free Radic Biol Med 88:337–349CrossRef
5.
Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD (2008) Dual roles of Nrf2 in cancer. Pharmacol Res 58:262–270CrossRef
6.
Pandey P, Singh AK, Singh M, Tewari M, Shukla HS, Gambhir IS (2017) The see-saw of Keap1-Nrf2 pathway in cancer. Crit Rev Oncol/Hematol 116:89–98CrossRef
7.
Menegon S, Columbano A, Giordano S (2016) The dual roles of NRF2 in cancer. Trends Mol Med 22:578–593CrossRef
8.
Goldstein LD, Lee J, Gnad F, Klijn C, Schaub A, Reeder J, Daemen A, Bakalarski CE, Holcomb T, Shames DS (2016) Recurrent loss of NFE2L2 exon 2 is a mechanism for Nrf2 pathway activation in human cancers. Cell Rep 16:2605–2617CrossRef
9.
Geismann C, Arlt A, Sebens S, Schäfer H (2014) Cytoprotection “gone astray”: Nrf2 and its role in cancer. Onco Targets Ther 7:1497–1518PubMedPubMedCentral
10.
Guo Y, Shen L (2017) Overexpression of NRF 2 is correlated with prognoses of patients with malignancies: a meta-analysis. Thorac Cancer 8:558–564CrossRef
11.
Wang L, Zhang C, Qin L, Xu J, Li X, Wang W, Kong L, Zhou T, Li X (2018) The prognostic value of NRF2 in solid tumor patients: a meta-analysis. Oncotarget 9:1257–1265PubMed
12.
Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin D, Piñeros M, Znaor A, Bray F (2019) Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 144:1941–1953CrossRef
13.
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269CrossRef
14.
Borenstein M, Hedges L, Higgins J, Rothstein H (2009) Introduction to meta-analysis. John Wiley & Sons Ltd, ChichesterCrossRef
15.
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560CrossRef
16.
Light R, Pillemer D (1984) Summing up: the science of reviewing research. Harvard University Press, Cambridge
17.
Light R, Singer J, Willett J (1994) The visual presentation and interpretation of meta-analyses. In: Cooper H, Hedges LV (eds) The handbook of research synthesis. Russell Sage Foundation, New York, pp 439–445
18.
Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634CrossRef
19.
Duval S, Tweedie R (2000) A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. J Am Stat Assoc 95:89–98
20.
Duval S, Tweedie R (2000) Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56:455–463CrossRef
21.
Bekele RT, Venkatraman G, Liu R-Z, Tang X, Mi S, Benesch MG, Mackey JR, Godbout R, Curtis JM, McMullen TP (2016) Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance. Sci Rep 6:21164CrossRef
22.
Cha YJ, Jung WH, Koo JS (2017) Differential site-based expression of pentose phosphate pathway-related proteins among breast cancer metastases. Dis Markers 2017:7062517PubMedPubMedCentral
23.
Onodera Y, Motohashi H, Takagi K, Miki Y, Shibahara Y, Watanabe M, Ishida T, Hirakawa H, Sasano H, Yamamoto M (2014) NRF2 immunolocalization in human breast cancer patients as a prognostic factor. Endocr Relat Cancer 21:241–252CrossRef
24.
Xiao Y, Hu G, Dong D-D, Tian W, Li T-T, Jiang X-H, Wang L (2016) Prognostic value of NRF2 in breast cancer patients and its role as a tumor suppressor by directly inhibiting HER2 expression. Int J Clin Exp Pathol 9:4292–4306
25.
Wolf B, Goebel G, Hackl H, Fiegl H (2016) Reduced mRNA expression levels of NFE2L2 are associated with poor outcome in breast cancer patients. BMC Cancer 16:821CrossRef
26.
Zhang C, Wang H-J, Bao Q-C, Wang L, Guo T-K, Chen W-L, Xu L-L, Zhou H-S, Bian J-L, Yang Y-R (2016) NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA/ROCK pathway signal transduction. Oncotarget 7:73593–73606PubMedPubMedCentral
27.
Bocci F, Tripathi SC, Mercedes SV, George JT, Casabar J, Wong PK, Hanash S, Levine H, Onuchic JN, Jolly MK (2018) NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype. biorxiv 11(6):251–263
28.
Zhang DD (2006) Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38:769–789CrossRef
29.
Zhang DD (2010) The Nrf2-Keap1-ARE signaling pathway: the regulation and dual function of Nrf2 in cancer. Antioxid Redox Signal 13:1623–16266CrossRef
30.
Curtis C, Shah SP, Chin S-F, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y (2012) The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 486:346–352CrossRef
31.
Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients. Breast Cancer Res Treat 123:725–731CrossRef
32.
Győrffy B, Surowiak P, Budczies J, Lánczky A (2013) Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS ONE 8:e82241CrossRef
33.
Weigman VJ, Chao H-H, Shabalin AA, He X, Parker JS, Nordgard SH, Grushko T, Huo D, Nwachukwu C, Nobel A (2012) Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival. Breast Cancer Res Treat 133:865–880CrossRef
Metadata
Title
The prognostic value of NRF2 in breast cancer patients: a systematic review with meta-analysis
Authors
Micaela Almeida
Mafalda Soares
Ana Cristina Ramalhinho
José Fonseca Moutinho
Luiza Breitenfeld
Luísa Pereira
Publication date
01-02-2020
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-019-05494-4

Other articles of this Issue 3/2020

Breast Cancer Research and Treatment 3/2020 Go to the issue

Preclinical study

Spectrum and clinical relevance of PALB2 germline mutations in 7657 Chinese BRCA1/2-negative breast cancer patients

Letter to the Editor

Do multifocal or multicentric pT1a node-negative HER2+ breast cancers get benefit from systemic treatment?

Letter to the Editor

Proper treatment of breast angiosarcoma-mastectomy or breast conserving surgery?

Clinical trial

The influence on quality of life of intermittent scheduling in first- and second-line chemotherapy of patients with HER2-negative advanced breast cancer

Clinical trial

Results of a phase I, non-randomized study evaluating a Magnetic Occult Lesion Localization Instrument (MOLLI) for excision of non-palpable breast lesions

Preclinical Study

The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits