title: The prognostic role of TGF-β signaling pathway in breast cancer patients.
abstract: BACKGROUND
  The transforming growth factor-β (TGF-β) pathway has dual effects on tumor growth. Seemingly, discordant results have been published on the relation between TGF-β signaling markers and prognosis in breast cancer. Improved prognostic information for breast cancer patients might be obtained by assessing interactions among TGF-β signaling biomarkers.
  
  
  METHODS
  The expression of nuclear Smad4, nuclear phosphorylated-Smad2 (p-Smad2), and the membranous expression of TGF-β receptors I and II (TβRI and TβRII) was determined on a tissue microarray of 574 breast carcinomas. Tumors were stratified according to the Smad4 expression in combination with p-Smad2 expression or Smad4 in combination with the expression of both TGF-β receptors.
  
  
  RESULTS
  Tumors with high expression of TβRII, TβRI and TβRII, and p-Smad2 (P = 0.018, 0.005, and 0.022, respectively), and low expression of Smad4 (P = 0.005) had an unfavorable prognosis concerning progression-free survival. Low Smad4 expression combined with high p-Smad2 expression or low expression of Smad4 combined with high expression of both TGF-β receptors displayed an increased hazard ratio of 3.04 [95% confidence interval (CI) 1.390-6.658] and 2.20 (95% CI 1.464-3.307), respectively, for disease relapse.
  
  
  CONCLUSIONS
  Combining TGF-β biomarkers provides prognostic information for patients with stage I-III breast cancer. This can identify patients at increased risk for disease recurrence that might therefore be candidates for additional treatment.
authors.affiliation: Departments of Surgery.
authors.forename: E M
authors.initials: EM
authors.lastname: de Kruijf
authors.affiliation: Departments of Surgery; Departments of Medical Oncology.
authors.forename: T J A
authors.initials: TJA
authors.lastname: Dekker
authors.affiliation: Molecular Cell Biology and Centre for Biomedical Genetics.
authors.forename: L J A C
authors.initials: LJAC
authors.lastname: Hawinkels
authors.affiliation: Medical Statistics.
authors.forename: H
authors.initials: H
authors.lastname: Putter
authors.affiliation: Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: V T H B M
authors.initials: VTHBM
authors.lastname: Smit
authors.affiliation: Departments of Medical Oncology.
authors.forename: J R
authors.initials: JR
authors.lastname: Kroep
authors.affiliation: Departments of Surgery.
authors.forename: P J K
authors.initials: PJK
authors.lastname: Kuppen
authors.affiliation: Departments of Surgery.
authors.forename: C J H
authors.initials: CJH
authors.lastname: van de Velde
authors.affiliation: Molecular Cell Biology and Centre for Biomedical Genetics; Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Ten Dijke
authors.affiliation: Departments of Surgery.
authors.forename: R A E M
authors.initials: RAEM
authors.lastname: Tollenaar
authors.affiliation: Departments of Surgery. Electronic address: w.e.mesker@lumc.nl.
authors.forename: W E
authors.initials: WE
authors.lastname: Mesker
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000096:biosynthesis / Q000378:metabolism*; D051901:Smad4 Protein / Q000096:biosynthesis / Q000378:metabolism*; D046888:Tissue Array Analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human