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. 2005 Aug 31;95(8):662–665. doi: 10.1111/j.1349-7006.2004.tb03326.x

Dominant‐negative Stat5 inhibits growth and induces apoptosis in T47D‐derived tumors in nude mice

Hiroko Yamashita 1,, Mariko Nishio 2, Yoshitaka Fujii 1, Hirotaka Iwase 2
PMCID: PMC11160093  PMID: 15298729

Abstract

Signal transducer and activator of transcription 5 (StatS) regulates growth, differentiation, and survival of mammary and hematopoietic cells. The role of Stat5 in breast cancer has not been established, although Stat5 is critical for some hematopoietic maignancies. In this study, we have analyzed the role of Stat5 in progression of the estrogen receptor‐positive T47D human breast cancer cell line, in which Stat5b is constitutively activated. Expression of Stat5‐regulated genes, such as cyclin D1 and bcl‐xL, was strongly suppressed in T47D cells infected with the dominant‐negative Stat5 adenovirus, AdStat5aA740. We also determined the phenotypic effects of introduction of dominant‐negative Stat5 on T47D‐derived tumors in nude mice. Tumors injected with AdStat5aA740 showed a 60% reduction in size, which was associated with the induction of apoptosis. Our results indicate the possibility of using dominant‐negative Stat5 to induce apoptosis in certain Stat5‐activated breast cancers.

References

  • 1. Hennighausen L, Robinson GW, Wagner KU, Liu W. Prolactin signaling in mammary gland development. J Biol Chem 1997; 272: 7567–9. [DOI] [PubMed] [Google Scholar]
  • 2. Watson CJ. Stat transcription factors in mammary gland development and tumorigenesis. J Mammary Gland Biol Neoplasia 2001; 6: 115–27. [DOI] [PubMed] [Google Scholar]
  • 3. Grimley PM, Dong F, Rui H. Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation. Cytokine Growth Factor Rev 1999; 10: 131–57. [DOI] [PubMed] [Google Scholar]
  • 4. Bromberg J. Stat proteins and oncogenesis. J Clin Invest 2002; 109: 1139–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 2002; 8: 945–54. [PubMed] [Google Scholar]
  • 6. Yamashita H, Iwase H. The role of Stat5 in estrogen receptor‐positive breast cancer. Breast Cancer 2002; 9: 312–8. [DOI] [PubMed] [Google Scholar]
  • 7. Yamashita H, Iwase H, Toyama T, Fujii Y Naturally occurring dominant‐negative Stat5 suppresses transcriptional activity of estrogen receptors and induces apoptosis in T47D breast cancer cells. Oncogene 2003; 22: 1638–52. [DOI] [PubMed] [Google Scholar]
  • 8. Jones N, Shenk T. Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells. Cell 1979; 17: 683–9. [DOI] [PubMed] [Google Scholar]
  • 9. Battle TE, Frank DA. The role of STATs in apoptosis. Curr Mol Med 2002; 2: 381–92. [DOI] [PubMed] [Google Scholar]
  • 10. Matsumura I, Ishikawa J, Nakajima K, Oritani K, Tomiyama Y, Miyagawa J, Kato T, Miyazaki H, Matsuzawa Y, Kanakura Y. Thrombopoietin‐induced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21(WAFl/Cipl) by STAT5. Mol Cell Biol 1997; 17: 2933–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Gartel AL, Tyner AL. The role of the cyclin‐dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 2002; 1: 639–49. [PubMed] [Google Scholar]
  • 12. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989; 342: 705–8. [DOI] [PubMed] [Google Scholar]
  • 13. Gesbert F, Griffin JD. Bcr/Abl activates transcription of the Bcl‐X gene through STAT5. Blood 2000; 96: 2269–76. [PubMed] [Google Scholar]
  • 14. Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF. Fetal anemia and apoptosis of red cell progenitors in Stat5a‐′‐Sb‐′‐mice: a direct role for Stat5 in Bcl‐X(L) induction. Cell 1999; 98: 181–91. [DOI] [PubMed] [Google Scholar]
  • 15. Matsumura I, Kitamura T, Wakao H, Tanaka H, Hashimoto K, Albanese C, Downward J, Pestell RG, Kanakura Y. Transcriptional regulation of the cyclin Dl promoter by STAT5: its involvement in cytokine‐dependent growth of hematopoietic cells. EMBO J 1999; 18: 1367–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Castro‐Rivera E, Samudio I, Safe S. Estrogen regulation of cyclin Dl gene expression in ZR‐75 breast cancer cells involves multiple enhancer elements. J Biol Chem 2001; 276: 30853–61. [DOI] [PubMed] [Google Scholar]
  • 17. Brockman JL, Schroeder MD, Schuler LA. PRL activates the cyclin Dl promoter via the Jak2/Stat pathway. Mol Endocrinol 2002; 16: 774–84. [DOI] [PubMed] [Google Scholar]

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