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.

Analysis of the association of TXNRD1 and TXNIP RNA expression with 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.

TXNRD1 was associated with worse MFI in the combined cohort (HR = 1.955; P < 0.001) as well as in all three individual cohorts. In contrast, TXNIP was associated with better prognosis (HR = 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 did not only cause 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.

TXNRD1 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 unfavourable manner.

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