title: The thioredoxin system in breast cancer cell invasion and migration.
abstract: Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1) in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1) expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS) or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS) levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration.
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, Brisbane, Qld. 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld. 4111, Australia.
authors.forename: Maneet
authors.initials: M
authors.lastname: Bhatia
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, Brisbane, Qld. 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld. 4111, Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: McGrath
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, Brisbane, Qld. 4111, Australia.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Di Trapani
authors.affiliation: Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innrain 80, 6020 Innsbruck, Austria.
authors.forename: Pornpimol
authors.initials: P
authors.lastname: Charoentong
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, Brisbane, Qld. 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld. 4111, Australia.
authors.forename: Fenil
authors.initials: F
authors.lastname: Shah
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, Brisbane, Qld. 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld. 4111, Australia.
authors.forename: Mallory M
authors.initials: MM
authors.lastname: King
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, Brisbane, Qld. 4111, Australia.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Clarke
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, Brisbane, Qld. 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld. 4111, Australia.
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Tonissen
mesh_terms: D001310:Auranofin / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D010084:Oxidation-Reduction; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000235:genetics* / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics* / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D017382:Reactive Oxygen Species; D001310:Auranofin; D013879:Thioredoxins; D054481:Thioredoxin Reductase 1
keywords: Auranofin; Breast cancer; Cell invasion; Cell migration; Patient survival; Thioredoxin