title: Redox protein expression predicts radiotherapeutic response in early-stage invasive breast cancer patients.
abstract: OBJECTIVE
  Early-stage invasive breast cancer patients have commonly undergone breast-conserving surgery and radiotherapy. In a large majority of these patients, the treatment is effective; however, a proportion will develop local recurrence. Deregulated redox systems provide cancer cells protection from increased oxidative stress, such as that induced by ionizing radiation. Therefore, the expression of redox proteins was examined in tumor specimens from this defined cohort to determine whether such expression could predict response.
  
  
  METHODS
  The nuclear and cytoplasmic expression of nine redox proteins (glutathione, glutathione reductase, glutaredoxin, glutathione peroxidase 1, 3, and 4, and glutathione S-transferase-θ, -π, and -α) was assessed using conventional immunohistochemistry on a tissue microarray of 224 tumors.
  
  
  RESULTS
  A high cytoplasmic expression of glutathione S-transferase-θ significantly correlated with a greater risk of local recurrence (p = .008) and, when combined with a low nuclear expression (p = .009), became an independent predictive factor (p = .002) for local recurrence. High cytoplasmic expression of glutathione S-transferase-θ also correlated with a worse overall survival (p = .009). Low nuclear and cytoplasmic expression of glutathione peroxidase 3 (p = .002) correlated with a greater risk of local recurrence and was an independent predictive factor (p = .005). These proteins did not correlate with tumor grade, suggesting their function might be specific to the regulation of oxidative stress rather than alterations of tumor phenotype. Only nuclear (p = .005) and cytoplasmic (p = .001) expression of glutathione peroxidase 4 correlated with the tumor grade.
  
  
  CONCLUSIONS
  Our results support the use of redox protein expression, namely glutathione S-transferase-θ and glutathione peroxidase 3, to predict the response to radiotherapy in early-stage breast cancer patients. If incorporated into routine diagnostic tests, they have the potential to aid clinicians in their stratification of patients into more tailored treatment regimens. Future targeted therapies to these systems might improve the efficacy of reactive oxygen species-inducing therapies, such as radiotherapy.
authors.affiliation: Division of Clinical Oncology, University of Nottingham School of Molecular Medical Sciences, Nottingham, United Kingdom.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Woolston
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Attar
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Storr
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: David A L
authors.initials: DA
authors.lastname: Morgan
authors.forename: Stewart G
authors.initials: SG
authors.lastname: Martin
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D054477:Glutaredoxins / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000201:enzymology*; D009367:Neoplasm Staging; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016896:Treatment Outcome
chemical_list: D054477:Glutaredoxins; D007527:Isoenzymes; D009363:Neoplasm Proteins; C486484:GPX3 protein, human; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; C413545:glutathione S-transferase T1; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha