This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xi, S. Articles by Grandis, J. R. Search for Related Content PubMed PubMed Citation Articles by Xi, S. Articles by Grandis, J. R.

Constitutive Activation of Stat5b Contributes to Carcinogenesis in Vivo

Departments of Otolaryngology [S. X., J. R. G.], Pharmacology [Q. Z., J. R. G.], and Molecular Genetics and Biochemistry [T. E. S.], University of Pittsburgh School of Medicine, and Department of Biostatistics, University of Pittsburgh Cancer Institute [W. E. G.], Pittsburgh, Pennsylvania 15213

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.

This article has been cited by other articles:

				A. A. Nemec and A. Barchowsky Signal Transducer and Activator of Transcription 1 (STAT1) is Essential for Chromium Silencing of Gene Induction in Human Airway Epithelial Cells Toxicol. Sci., July 1, 2009; 110(1): 212 - 223. [Abstract] [Full Text] [PDF]

				A. Hosui, A. Kimura, D. Yamaji, B.-m. Zhu, R. Na, and L. Hennighausen Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation J. Exp. Med., April 13, 2009; 206(4): 819 - 831. [Abstract] [Full Text] [PDF]

				P. Koppikar, V. W. Y. Lui, D. Man, S. Xi, R. L. Chai, E. Nelson, A. B.J. Tobey, and J. R. Grandis Constitutive Activation of Signal Transducer and Activator of Transcription 5 Contributes to Tumor Growth, Epithelial-Mesenchymal Transition, and Resistance to Epidermal Growth Factor Receptor Targeting Clin. Cancer Res., December 1, 2008; 14(23): 7682 - 7690. [Abstract] [Full Text] [PDF]

				E. M. Fox, T. M. Bernaciak, J. Wen, A. M. Weaver, M. A. Shupnik, and C. M. Silva Signal Transducer and Activator of Transcription 5b, c-Src, and Epidermal Growth Factor Receptor Signaling Play Integral Roles in Estrogen-Stimulated Proliferation of Estrogen Receptor-Positive Breast Cancer Cells Mol. Endocrinol., August 1, 2008; 22(8): 1781 - 1796. [Abstract] [Full Text] [PDF]

				B. Basham, M. Sathe, J. Grein, T. McClanahan, A. D'Andrea, E. Lees, and A. Rascle In vivo identification of novel STAT5 target genes Nucleic Acids Res., June 1, 2008; 36(11): 3802 - 3818. [Abstract] [Full Text] [PDF]

				K. M. Mohankumar, J. K. Perry, N. Kannan, K. Kohno, P. D. Gluckman, B. S. Emerald, and P. E. Lobie Transcriptional Activation of Signal Transducer and Activator of Transcription (STAT) 3 and STAT5B Partially Mediate Homeobox A1-Stimulated Oncogenic Transformation of the Immortalized Human Mammary Epithelial Cell Endocrinology, May 1, 2008; 149(5): 2219 - 2229. [Abstract] [Full Text] [PDF]

				F. A. Mallette, M.-F. Gaumont-Leclerc, G. Huot, and G. Ferbeyre Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence J. Biol. Chem., November 30, 2007; 282(48): 34938 - 34944. [Abstract] [Full Text] [PDF]

				J. R. Grandis, J. Califano, I. Smith, and S. Mithani Response: Re: Decreased STAT1 Expression by Promoter Methylation in Squamous Cell Carcinogenesis J Natl Cancer Inst, September 5, 2007; 99(17): 1344 - 1344. [Full Text] [PDF]

				T. Lahusen, M. Fereshteh, A. Oh, A. Wellstein, and A. T. Riegel Epidermal Growth Factor Receptor Tyrosine Phosphorylation and Signaling Controlled by a Nuclear Receptor Coactivator, Amplified in Breast Cancer 1 Cancer Res., August 1, 2007; 67(15): 7256 - 7265. [Abstract] [Full Text] [PDF]

				T. K.S. Ku, D. C. Nguyen, M. Karaman, P. Gill, J. G. Hacia, and D. L. Crowe Loss of p53 Expression Correlates with Metastatic Phenotype and Transcriptional Profile in a New Mouse Model of Head and Neck Cancer Mol. Cancer Res., April 1, 2007; 5(4): 351 - 362. [Abstract] [Full Text] [PDF]

				J. Shen, C. Behrens, I. I. Wistuba, L. Feng, J. J. Lee, W. K. Hong, and R. Lotan Identification and Validation of Differences in Protein Levels in Normal, Premalignant, and Malignant Lung Cells and Tissues Using High-Throughput Western Array and Immunohistochemistry Cancer Res., December 1, 2006; 66(23): 11194 - 11206. [Abstract] [Full Text] [PDF]

				T. K. Lee, K. Man, R. T.P. Poon, C. M. Lo, A. P. Yuen, I. O. Ng, K. T. Ng, W. Leonard, and S. T. Fan Signal Transducers and Activators of Transcription 5b Activation Enhances Hepatocellular Carcinoma Aggressiveness through Induction of Epithelial-Mesenchymal Transition. Cancer Res., October 15, 2006; 66(20): 9948 - 9956. [Abstract] [Full Text] [PDF]

				A. M. Weaver and C. M. Silva Modulation of Signal Transducer and Activator of Transcription 5b Activity in Breast Cancer Cells by Mutation of Tyrosines within the Transactivation Domain Mol. Endocrinol., October 1, 2006; 20(10): 2392 - 2405. [Abstract] [Full Text] [PDF]

				S. Kalyankrishna and J. R. Grandis Epidermal Growth Factor Receptor Biology in Head and Neck Cancer J. Clin. Oncol., June 10, 2006; 24(17): 2666 - 2672. [Abstract] [Full Text] [PDF]

				H. Lee and H. Yu Methylation of Stat1 Promoter Can Contribute to Squamous Cell Carcinogenesis J Natl Cancer Inst, February 1, 2006; 98(3): 154 - 155. [Full Text] [PDF]

				S. Xi, K. F. Dyer, M. Kimak, Q. Zhang, W. E. Gooding, J. R. Chaillet, R. L. Chai, R. E. Ferrell, B. Zamboni, J. Hunt, et al. Decreased STAT1 Expression by Promoter Methylation in Squamous Cell Carcinogenesis J Natl Cancer Inst, February 1, 2006; 98(3): 181 - 189. [Abstract] [Full Text] [PDF]

				M. Shi, J. C. Cooper, and C.-L. Yu A Constitutively Active Lck Kinase Promotes Cell Proliferation and Resistance to Apoptosis through Signal Transducer and Activator of Transcription 5b Activation Mol. Cancer Res., January 1, 2006; 4(1): 39 - 45. [Abstract] [Full Text] [PDF]

				T. Phung-Koskas, A. Pilon, C. Pous, C. Betzina, M. Sturm, M.-L. Bourguet-Kondracki, G. Durand, and A. Drechou STAT5B-mediated Growth Hormone Signaling Is Organized by Highly Dynamic Microtubules in Hepatic Cells J. Biol. Chem., January 14, 2005; 280(2): 1123 - 1131. [Abstract] [Full Text] [PDF]

				R. Gonsky, R. L. Deem, J. Bream, H. A. Young, and S. R. Targan Enhancer Role of STAT5 in CD2 Activation of IFN-{gamma} Gene Expression J. Immunol., November 15, 2004; 173(10): 6241 - 6247. [Abstract] [Full Text] [PDF]