title: Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes.
abstract: BACKGROUND
  Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome.
  
  
  METHODS
  Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models.
  
  
  RESULTS
  Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome.
  
  
  CONCLUSIONS
  Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Peck
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Chengbao
authors.initials: C
authors.lastname: Liu
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Klimowicz
authors.forename: Ginger A
authors.initials: GA
authors.lastname: Stringer
authors.forename: Edward
authors.initials: E
authors.lastname: Pequignot
authors.forename: Boris
authors.initials: B
authors.lastname: Freydin
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Thai H
authors.initials: TH
authors.lastname: Tran
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Girondo
authors.forename: Anne L
authors.initials: AL
authors.lastname: Rosenberg
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hooke
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kovatich
authors.forename: Craig D
authors.initials: CD
authors.lastname: Shriver
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Magliocco
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D002467:Cell Nucleus / Q000378:metabolism; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D010766:Phosphorylation; D011379:Prognosis; D021381:Protein Transport; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D050799:STAT5 Transcription Factor