Abstract
IntroductionThe purpose of this work was to study the prognostic influence in breast cancer of thioredoxin reductase 1 (TXNRD1) and thioredoxin interacting protein (TXNIP), key players in oxidative stress control that are currently evaluated as possible therapeutic targets.MethodsAnalysis of the association of TXNRD1 and TXNIP RNA expression with the metastasis-free interval (MFI) was performed in 788 patients with node-negative breast cancer, consisting of three individual cohorts (Mainz, Rotterdam and Transbig). Correlation with metagenes and conventional clinical parameters (age, pT stage, grading, hormone and ERBB2 status) was explored. MCF-7 cells with a doxycycline-inducible expression of an oncogenic ERBB2 were used to investigate the influence of ERBB2 on TXNRD1 and TXNIP transcription.ResultsTXNRD1 was associated with worse MFI in the combined cohort (hazard ratio = 1.955; P < 0.001) as well as in all three individual cohorts. In contrast, TXNIP was associated with better prognosis (hazard ratio = 0.642; P < 0.001) and similar results were obtained in all three subcohorts. Interestingly, patients with ERBB2-status-positive tumors expressed higher levels of TXNRD1. Induction of ERBB2 in MCF-7 cells caused not only an immediate increase in TXNRD1 but also a strong decrease in TXNIP. A subsequent upregulation of TXNIP as cells undergo senescence was accompanied by a strong increase in levels of reactive oxygen species.ConclusionsTXNRD1 and TXNIP are associated with prognosis in breast cancer, and ERBB2 seems to be one of the factors shifting balances of both factors of the redox control system in a prognostic unfavorable manner.
Highlights
The purpose of this work was to study the prognostic influence in breast cancer of thioredoxin reductase 1 (TXNRD1) and thioredoxin interacting protein (TXNIP), key players in oxidative stress control that are currently evaluated as possible therapeutic targets
TXNDR1 and TXNIP are associated with prognosis in breast cancer To study a possible association with the metastasis-free interval (MFI), we analyzed our cohort (Mainz cohort) of patients and validated the results in two previously published cohorts (Rotterdam and Transbig cohorts)
The results demonstrate that expression of TXNIP and TXNRD1, the two factors influencing the thioredoxin pathway, and downstream effectors show prognostic relevance in breast cancer (Table 4): thioredoxin (TXN), the M2 subunit of ribonucleotide reductase (RRM2), peroxiredoxin 2 (PRDX2), HIF-1α and vascular endothelial growth factor (VEGF) were significantly associated with worse prognosis in the combined cohort as well as in at least one of the studied cohorts
Summary
The purpose of this work was to study the prognostic influence in breast cancer of thioredoxin reductase 1 (TXNRD1) and thioredoxin interacting protein (TXNIP), key players in oxidative stress control that are currently evaluated as possible therapeutic targets. ROS contribute to tumor progression by amplifying genomic instability but transformed cells use ROS signals to drive proliferation [1]. Thioredoxin reductase 1 (TXNRD1) and thioredoxin interacting protein (TXNIP; called thioredoxin binding protein 2 or vitamin D3-upregulated protein 1) [5] are key players in oxidative stress control. In addition to its critical role in the regulation of cellular redox homeostasis, thioredoxin has multiple actions in the cell - such as activation of ribonucleotide reductase, inhibition of apoptosis signal regulating kinase 1 and induction of hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) - which contribute to many hallmarks of cancer, such as increased proliferation, inhibited apoptosis and angiogenesis [8]
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