title: Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure.
abstract: OBJECTIVE
  To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy.
  
  
  METHODS
  Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays.
  
  
  RESULTS
  Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). CONCLUSION Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy.
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St, Philadelphia, PA 19107, USA.
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: Ginger A
authors.initials: GA
authors.lastname: Stringer
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Klimowicz
authors.forename: Edward
authors.initials: E
authors.lastname: Pequignot
authors.forename: Boris
authors.initials: B
authors.lastname: Freydin
authors.forename: Thai H
authors.initials: TH
authors.lastname: Tran
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
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: Marja T
authors.initials: MT
authors.lastname: Nevalainen
authors.forename: Craig D
authors.initials: CD
authors.lastname: Shriver
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Magliocco
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry; D011379:Prognosis; D011499:Protein Processing, Post-Translational; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000502:physiology*; D016019:Survival Analysis; D017211:Treatment Failure; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000502:physiology*; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins; D019000:Phosphotyrosine