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The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells

Nature volume 406, pages 742–747 (2000)Cite this article

Abstract

Syk is a protein tyrosine kinase that is widely expressed in haematopoietic cells. It is involved in coupling activated immunoreceptors to downstream signalling events that mediate diverse cellular responses including proliferation, differentiation and phagocytosis1,2,3,4. Syk expression has been reported in cell lines of epithelial origin5, but its function in these cells remains unknown. Here we show that Syk is commonly expressed in normal human breast tissue, benign breast lesions and low-tumorigenic breast cancer cell lines. Syk messenger RNA and protein, however, are low or undetectable in invasive breast carcinoma tissue and cell lines. Transfection of wild-type Syk into a Syk-negative breast cancer cell line markedly inhibited its tumour growth and metastasis formation in athymic mice. Conversely, overexpression of a kinase-deficient Syk in a Syk-positive breast cancer cell line significantly increased its tumour incidence and growth. Suppression of tumour growth by the reintroduction of Syk appeared to be the result of aberrant mitosis and cytokinesis. We propose that Syk is a potent modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas.

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Figure 1: Syk expression in human breast cancer cell lines.
Figure 2: Syk expression in normal and pathological human breast tissue samples.
Figure 3: Effect of Syk transfection on tumorigenesis and metastasis formation in vivo.
Figure 4: Biological consequences of Syk transfection in MDA-MB-435 cells.

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References

  1. Cheng, A. M. & Chan, A. C. Protein tyrosine kinases in thymocyte development. Curr. Opin. Immunol. 9, 528 –533 (1997).

    Article  CAS  Google Scholar 

  2. Kurosaki, T. Molecular mechanisms in B cell antigen receptor signaling. Curr. Opin. Immunol. 9, 309–318 (1997).

    Article  CAS  Google Scholar 

  3. Chu, D. H., Morita, C. T. & Weiss, A. The Syk family of protein tyrosine kinases in T-cell activation and development. Immunol. Rev. 165, 167–180 (1998).

    Article  CAS  Google Scholar 

  4. Indik, Z. K., Park, J. G., Pan, X. Q. & Schreiber, A. D. Induction of phagocytosis by a protein tyrosine kinase. Blood 85, 1175–1180 (1995).

    Article  CAS  Google Scholar 

  5. Fluck, M., Zurcher, G., Andres, A. C. & Ziemiecki, A. Molecular characterization of the murine Syk protein tyrosine kinase cDNA, transcripts and protein. Biochem. Biophys. Res. Commun. 213, 273–281 (1995).

    Article  CAS  Google Scholar 

  6. Coopman, P. J., Do, M. T. H., Thompson, E. W. & Mueller, S. C. Phagocytosis of cross-linked gelatin matrix by human breast carcinoma cells correlates with their invasive capacity. Clin. Canc. Res. 4, 507–515 (1998).

    CAS  Google Scholar 

  7. Coopman, P. J., Thomas, D. M., Gehlsen, K. R. & Mueller, S. C. Integrin α3β1 participates in the phagocytosis of extracellular matrix molecules by human breast cancer cells. Mol. Biol. Cell 7, 1789–1804 ( 1996).

    Article  CAS  Google Scholar 

  8. Thompson, E. W. et al. Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J. Cell Physiol. 150, 534– 544 (1992).

    Article  CAS  Google Scholar 

  9. Law, C. L. et al. Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex. J. Biol. Chem. 269, 12310–12319 (1994).

    Article  CAS  Google Scholar 

  10. Nagai, K., Inazu, T. & Yamamura, H. p72syk is activated by vanadate plus H2O 2 in porcine platelets and phosphorylates GTPase activating protein on tyrosine residue(s). J. Biochem. (Tokyo) 116, 1176–1181 (1994).

    Article  CAS  Google Scholar 

  11. Fargnoli, J. et al. Syk mutation in Jurkat E6-derived clones results in lack of p72syk expression. J. Biol. Chem. 270, 26533–26537 (1995).

    Article  CAS  Google Scholar 

  12. Brunner, N. et al. lacZ transduced human breast cancer xenografts as an in vivo model for the study of invasion and metastasis. Eur. J. Cancer 28A, 1989–1995 (1992).

    Article  CAS  Google Scholar 

  13. Kurebayashi, J. et al. Quantitative demonstration of spontaneous metastasis by MCF-7 human breast cancer cells cotransfected with fibroblast growth factor 4 and LacZ. Cancer Res. 53, 2178– 2187 (1993).

    CAS  PubMed  Google Scholar 

  14. Takata, M. et al. Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways. EMBO J. 13, 1341–1349 ( 1994).

    Article  CAS  Google Scholar 

  15. Peters, J. D., Furlong, M. T., Asai, D. J., Harrison, M. L. & Geahlen, R. L. Syk, activated by cross-linking the B-cell antigen receptor, localizes to the cytosol where it interacts with and phosphorylates alpha-tubulin on tyrosine. J. Biol. Chem. 271, 4755–4762 (1996).

    Article  CAS  Google Scholar 

  16. Lingle, W. L. & Salisbury, J. L. Altered centrosome structure is associated with abnormal mitoses in human breast tumors. Am. J. Pathol. 155, 1941–1951 (1999).

    Article  CAS  Google Scholar 

  17. Miranti, C. K., Leng, L., Maschberger, P., Brugge, J. S. & Shattil, S. J. Identification of a novel integrin signaling pathway involving the kinase Syk and the guanine nucleotide exchange factor Vav1. Curr. Biol. 8, 1289– 1299 (1998).

    Article  CAS  Google Scholar 

  18. Williams, S. et al. Reconstitution of T cell antigen receptor-induced Erk2 kinase activation in Lck-negative JCaM1 cells by Syk. Eur. J. Biochem. 245, 84–90 ( 1997).

    Article  CAS  Google Scholar 

  19. Deckert, M., Tartare-Deckert, S., Couture, C., Mustelin, T. & Altman, A. Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product. Immunity 5, 591–604 ( 1996).

    Article  CAS  Google Scholar 

  20. Law, C. L., Chandran, K. A., Sidorenko, S. P. & Clark, E. A. Phospholipase C-gamma1 interacts with conserved phosphotyrosyl residues in the linker region of Syk and is a substrate for Syk. Mol. Cell. Biol. 16, 1305–1315 ( 1996).

    Article  CAS  Google Scholar 

  21. Minobe, K. et al. Allelic loss on chromosome 9q is associated with lymph node metastasis of primary breast cancer. Jpn. J. Cancer Res. 89, 916–922 (1998).

    Article  ADS  CAS  Google Scholar 

  22. Turner, M. et al. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 378, 298–302 (1995).

    Article  ADS  CAS  Google Scholar 

  23. Cheng, A. M. et al. Syk tyrosine kinase required for mouse viability and B-cell development. Nature 378, 303– 306 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Murphy, M. A. et al. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl- deficient mice. Mol. Cell Biol. 18, 4872–4882 (1998).

    Article  CAS  Google Scholar 

  25. Schaeren-Wiemers, N. & Gerfin-Moser, A. A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100, 431– 440 (1993).

    Article  CAS  Google Scholar 

  26. Emmert-Buck, M. R. et al. Laser capture microdissection. Science 274, 998–1001 (1996).

    Article  ADS  CAS  Google Scholar 

  27. Yagi, S., Suzuki, K., Hasegawa, A., Okumura, K. & Ra, C. Cloning of the cDNA for the deleted Syk kinase homologous to Zap- 70 from human basophilic leukemia cell line (KU812). Biochem. Biophys. Res. Commun. 200, 28–34 (1994).

    Article  CAS  Google Scholar 

  28. Pinkel, D. et al. Cytogenetic analysis by in situ hybridization with fluorescently labeled nucleic acid probes. Cold Spring Harbor Symp. Quant. Biol. 51, 151–157 ( 1986).

    Article  CAS  Google Scholar 

  29. Fang, W., Hartmann, N., Chow, D. T., Riegel, A. T. & Wellstein, A. Pleiotrophin stimulates fibroblasts and endothelial and epithelial cells and is expressed in human cancer. J. Biol. Chem. 267, 25889–25897 (1992).

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge S. Yagi and T. Kurosaki who have provided the Syk cDNAs. We thank P. Burbelo for the pCAF1 vector; F. Kern for ML20 cells; J. Zwiebel for MDA-MB-435BAG cells; C. Theillet for tumour samples; A. Wright, F. Onajafe and M. Dai for technical assistance; S. Artero for statistics; and B. Singh and P. Roger for pathology advice. We also thank J. Brugge, N. Taylor, A. Wellstein and M. Lippman for comments on the manuscript. This work was supported in part by NIH grants (to S.C.M. and S.W.M.) and, in part, by the Lombardi Cancer Center shared resources supported by a US Public Health Service Grant.

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Author notes

  1. Peter J. P. Coopman

    Present address: Centre National de la Recherche Scientifique UMR 5539, Montpellier, France

Authors and Affiliations

  1. Department of Cell Biology, 20007, Washington DC, USA

    Peter J. P. Coopman, Michael T. H. Do, Mara Barth & Susette C. Mueller

  2. Department of Oncology, 20007, Washington DC, USA

    Emma T. Bowden, Andrew J. Hayes, Sandra W. McLeskey & Susette C. Mueller

  3. Department of Pathology, 20007, Washington DC, USA

    Phyllis R. Vezza

  4. Department of Pharmacology and School of Nursing, 20007, Washington DC, USA

    Sandra W. McLeskey

  5. Institute for Molecular and Human Genetics, and Vincent T. Lombardi Cancer Center, Georgetown University Medical School, 20007, Washington DC, USA

    Jan K. Blancato

  6. Centre National de la Recherche Scientifique UPR 9023, 20007, Washington DC, USA

    Eugenia Basyuk

  7. Centre National de la Recherche Scientifique UMR 5539, Montpellier, 34095, France

    Paul H. Mangeat

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Correspondence to Susette C. Mueller.

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Coopman, P., Do, M., Barth, M. et al. The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 406, 742–747 (2000). https://doi.org/10.1038/35021086

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