Advertisement

Involvement of a JAK/STAT Pathway Inhibitor: Cytokine Inducible SH2 Containing Protein in Breast Cancer

  • Sahra Borgés
  • Elara Moudilou
  • Cécile Vouyovitch
  • Jean Chiesa
  • Peter Lobie
  • Hichem Mertani
  • Mireille Raccurt
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)

Summary

Cytokines and growth factors are responsible for inducing the expression of suppressor of cytokine signaling (SOCS) and cytokine-inducible SH2 containing (CIS) proteins. SOCS and CIS proteins are negative regulators of the JAK/STAT pathway, and exert their physiological effects by suppressing the tyrosine kinase activity of cytokine receptors and inhibiting STAT activation. Growth hormone (GH) is considered as a true cytokine and its local production directly contributes to tumor progression. In an initial study, we have found that CIS expression is increased in human breast cancer in proliferative areas corresponding to high level of GH synthesis. The results of the study presented here confirm the presence of a negative feed back loop in MCF7 cells stably transfected with the hGH gene (MCF-hGH). Real-time PCR analysis showed that gene expression levels of CIS were increased by 80% in MCF-hGH cells as compared to control cell line. Similarly, we have found that the level of CIS gene expression is increased by 50% in primary cultures of human breast cancer, reinforcing the pathophysiological impact of CIS. We previously demonstrated that increasing levels of transfected CIS resulted in strong activation of the mitogen-activated protein (MAP) kinase pathway. Thus, CIS protein has been hypothesized as acting like an activator of the MAPK pathway and an inhibitor of the differentiated cells functions mediated through the JAK/STAT pathway. In the present study, we demonstrate the role of CIS protein in tumor progression in particular its positive effects on cell proliferation and colony formation.

Keywords

Growth Hormone Chronic Myeloid Leukemia Human Mammary Carcinoma Cell Growth Hormone Expression Growth Hormone Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ali S, Coombes RC (2002) Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2:101–12.PubMedCrossRefGoogle Scholar
  2. 2.
    Imada K, Leonard WJ (2000) The JAK/STATpathway. Mol Immunol. 37:1–11.PubMedCrossRefGoogle Scholar
  3. 3.
    Raccurt M, Lobie PE, Moudilou E, et al. (2002) High stromal and epithelial hGH gene expression is associated with proliferative disorders of the mammary gland. J. Endocrinol. 175: 307–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Mukhina S, Mertani HC, Guo K, et al. (2004) Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proc Natl Acad Sci USA 101:14992–3.CrossRefGoogle Scholar
  5. 5.
    Zhu T, Starling-Emerald B, Zhang X, et al. (2005) p44/42 MAP kinase-dependent regulation of catalase by autocrine human growth hormone protects human mammary carcinoma cells from oxidative stress-induced apoptosis. Oncogene 24:3774–85.PubMedCrossRefGoogle Scholar
  6. 6.
    Du L, G. Frick P, Tai LR, et al. (2003) Interaction of the growth hormone receptor with cytokine-induced Src homology domain 2 protein in rat adipocytes. Endocrinology 144:868–76.PubMedCrossRefGoogle Scholar
  7. 7.
    Kamio M, Yoshida T, Ogata H, et al. (2004) SOCS corrected inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein. Oncogene 23:3107–15.PubMedCrossRefGoogle Scholar
  8. 8.
    He B, You L, Xu Z, et al. (2004) Activity of the suppressor of cytokine signaling-3 promoter in human non-small-cell lung cancer. Clin Lung Cancer 5:366–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Li Z, Metze D, Nashan D, et al. (2004) Expression of SOCS-1, suppressor of cytokine signalling-1, in human melanoma. J Invest Dermatol 123:737–45.PubMedCrossRefGoogle Scholar
  10. 10.
    Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, et al. (2004) The suppressor of cytokine signaling-1 is constitutively expressed in chronic myeloid leukemia and correlates with poor cytogenetic response to interferon-alpha. Haematologica 89:42–8.PubMedGoogle Scholar
  11. 11.
    Raccurt M, Ping Tam, Lau P, et al. (2003) Suppressor of cytokine signalling gene expression is elevated in breast carcinoma. Brit J Cancer 89:524–32.PubMedCrossRefGoogle Scholar
  12. 12.
    Liu N, Mertani HC, Norstedt G, et al. (1997) Mode of the autocrine/paracrine mechanism of growth hormone action. Exp Cell Res 237:196–206.PubMedCrossRefGoogle Scholar
  13. 13.
    Ram PA, Waxman DJ (2000) Role of the cytokine-inducible SH2 protein CIS in desensitization of STAT5b signalling by continuous growth hormone. J Biol Chem 275:39487–96.PubMedCrossRefGoogle Scholar
  14. 14.
    Cooper JC, Boustead JN, Yu CL (2006) Characterization of STAT5B phosphorylation correlating with expression of cytokine-inducible SH2-containing protein (CIS). Cell Signal 18:851–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Campbell IL (2005) Cytokine-mediated inflammation, tumorigenesis, and disease-associated JAK/STAT/SOCS signaling circuits in the CNS. Brain Res Brain Res Rev 48:166–77.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Sahra Borgés
    • 1
  • Elara Moudilou
  • Cécile Vouyovitch
    • 2
  • Jean Chiesa
  • Peter Lobie
  • Hichem Mertani
    • 3
  • Mireille Raccurt
    • 4
  1. 1.Physiologie Integrative Cell. Et MolUniversite Claude BernardVilleurbanneFrance
  2. 2.Physiologie Intefrative Cell. MolUniversite Claude BernardVilleurbanneFrance
  3. 3.Physiologie MoleculaireUniversite Claude Bernard LyonlVilleurbanneFrance
  4. 4.Physiologie Integrative Cell. Et MolUniversite Claude Bernard Lyonl-43VilleurbanneFrance

Personalised recommendations