Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer

Although the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway is one of the most frequently dysregulated in cancer, it is not clear whether mutational status is a good predictor of NRF2 activity. Here we utilise four members of the aldo-keto reductase (AKR) superfamily as biomarkers to add...

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Bibliographic Details
Published in:British journal of cancer 2016-12, Vol.115 (12), p.1530-1539
Main Authors: MacLeod, A Kenneth, Acosta-Jimenez, Lourdes, Coates, Philip J, McMahon, Michael, Carey, Frank A, Honda, Tadashi, Henderson, Colin J, Wolf, C Roland
Format: Article
Language:English
Subjects:
Aldehyde Reductase - metabolism
Aldo-Keto Reductases
Biomarkers - metabolism
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Humans
Lung cancer
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Molecular Diagnostics
NF-E2-Related Factor 2 - metabolism
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Summary:Although the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway is one of the most frequently dysregulated in cancer, it is not clear whether mutational status is a good predictor of NRF2 activity. Here we utilise four members of the aldo-keto reductase (AKR) superfamily as biomarkers to address this question. Twenty-three cell lines of diverse origin and NRF2-pathway mutational status were used to determine the relationship between AKR expression and NRF2 activity. AKR expression was evaluated in lung cancer biopsies and Cancer Genome Atlas (TCGA) and Oncomine data sets. AKRs were expressed at a high basal level in cell lines carrying mutations in the NRF2 pathway. In non-mutant cell lines, co-ordinate induction of AKRs was consistently observed following activation of NRF2. Immunohistochemical analysis of lung tumour biopsies and interrogation of TCGA data revealed that AKRs are enriched in both squamous cell carcinomas (SCCs) and adenocarcinomas that contain somatic alterations in the NRF2 pathway but, in the case of SCC, AKRs were also enriched in most other tumours. An AKR biomarker panel can be used to determine NRF2 status in tumours. Hyperactivation of the NRF2 pathway is far more prevalent in lung SCC than previously predicted by genomic analyses.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2016.363