Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer.
BACKGROUND
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.


METHODS
Analysis 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.


RESULTS
TXNRD1 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.


CONCLUSIONS
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 unfavorable manner.
Cadenas
Cristina
C
Department of Bioanalytics, Leibniz-Institut für Analytische Wissenschaften-ISAS-e,V, Bunsen-Kirchhoff-Strasse 11, Dortmund, Germany. cristina.cadenas@isas.de
Franckenstein
Dennis
D
Schmidt
Marcus
M
Gehrmann
Mathias
M
Hermes
Matthias
M
Geppert
Bettina
B
Schormann
Wiebke
W
Maccoux
Lindsey J
LJ
Schug
Markus
M
Schumann
Anika
A
Wilhelm
Christian
C
Freis
Evgenia
E
Ickstadt
Katja
K
Rahnenführer
Jörg
J
Baumbach
Jörg I
JI
Sickmann
Albert
A
Hengstler
Jan G
JG
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015996:Survival Rate; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D054481:Thioredoxin Reductase 1; C486715:TXNIP protein, human; C516124:TXNRD1 protein, human; C508053:ERBB2 protein, human