Prognostic significance of signal transducer and activator of transcription 1 activation in breast cancer.
OBJECTIVE
Signal transducers and activators of transcription (STATs)were shown to be activated in mammary carcinoma. Because different STAT factors are likely to have different functions in these tumors, an assessment of their individual role is mandatory.


METHODS
In this study we have separately determined activation of STAT1, STAT3, and STAT5 by measuring their DNA binding activity and tyrosine phosphorylation in breast cancer tissue samples. The predictive value of STAT activation on relapse-free and overall survival among women who received treatment for primary breast cancer was evaluated in a retrospective study.


RESULTS
Survival analysis demonstrated that patients with high STAT1 activation have substantially longer overall and relapse-free survival, irrespective of whether STAT1 activation was determined by its DNA binding activity (P = 0.003 and 0.010, respectively) or by its tyrosine phosphorylation (P = 0.046 and 0.011, respectively). In accordance, Cox proportional hazard regression analysis revealed an enhanced hazard of death (hazard ratio, 3.77; P = 0.018) and relapse of disease (hazard ratio, 6.55; P = 0.013) for the group of women with low STAT1 activation. After adjusting for known prognostic variables (lymph node status, stage of disease, estrogen receptor status, and cathepsin D), STAT1 activation remained an independent prognostic value. Activation of STAT3 and STAT5 DNA binding did not significantly correlate with prognosis.


CONCLUSIONS
Our study reveals a favorable and independent prognostic significance of STAT1 activation in mammary carcinoma, and is in accordance with the documented role of STAT1 in growth arrest, and in pro-apoptotic signaling pathways.
Widschwendter
Andreas
A
Department of Obstetrics and Gynecology and Institute of Medical Chemistry and Biochemistry University of Innsbruck, A-6020 Innsbruck, Austria.
Tonko-Geymayer
Sibylle
S
Welte
Thomas
T
Daxenbichler
Günter
G
Marth
Christian
C
Doppler
Wolfgang
W
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D008894:Milk Proteins; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics*; D014443:Tyrosine / Q000378:metabolism
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D008894:Milk Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; C494079:STAT1 protein, human; C494086:STAT3 protein, human