Constitutive activation of Stat5b contributes to carcinogenesis in vivo.
The development of more effective prevention and treatment strategies for solid tumors is limited by an incomplete understanding of the critical growth pathways that are activated in carcinogenesis. Signal transducers and activators of transcription (STAT) proteins have been linked to transformation and tumor progression. Studies to date have not elucidated clear and distinct roles for Stat5genes (Stat5a and Stat5b) in human epithelial cancers. We analyzed the role of Stat5a/b isoforms in squamous cell carcinoma of the head and neck using expression and activation studies in human tissues and in a xenograft model after selective targeting. In a xenograft model, blockade of Stat5b, but not Stat5a, using antisense oligonucleotides resulted in tumor growth inhibition and abrogation of Stat5 target genes in vivo. Blockade of the epidermal growth factor receptor resulted in partial abrogation of Stat5 activation, thus linking epidermal growth factor receptor to Stat5 in vivo. In tissues from 33 individuals with head and neck cancer, Stat5 activation levels were correlated with progression to a malignant phenotype, where increased expression and phosphorylation of Stat5b were detected consistently in tumors compared with their epithelial counterparts. Thus, constitutive activation of Stat5b contributes to squamous cell tumorigenesis and may serve as a therapeutic target.
Departments of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Sichuan
S
Xi
Qing
Q
Zhang
William E
WE
Gooding
Thomas E
TE
Smithgall
Jennifer Rubin
JR
Grandis
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008894:Milk Proteins; D010766:Phosphorylation; D020033:Protein Isoforms; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D020033:Protein Isoforms; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors