Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways

Oncogene volume 22, pages 1198–1205 (2003)Cite this article

Abstract

Osteopontin (OPN) is a secreted, integrin-binding glycophosphoprotein that has been implicated in breast cancer. We previously showed that OPN-induced cell migration of mammary epithelial cells (MEC) depends on binding to cell surface integrins and involves activation of the hepatocyte growth factor (HGF) receptor, Met. Here, we show that OPN-induced migration of MEC also requires activation of the epidermal growth factor (EGF) pathway. Synergism was seen between EGF and OPN in inducing cell migration. Furthermore, incubation of cells with exogenous OPN increased ligand (TGFα> EGF) and EGF receptor (EGFR) mRNA expression, as well as EGFR kinase activity. Treatment of cells with anti-TGFα or anti-EGFR antibody, or with tyrphostin-25 (EGFR inhibitor), significantly impaired the cell migration response to OPN. Other more broad-spectrum tyrosine kinase inhibitors and the growth factor/ receptor interaction inhibitor, suramin, also inhibited OPN-induced migration. Using specific signal transduction pathway inhibitors, we have screened for involvement of MEK (MAP kinase kinase), phosphatidylinositol 3-kinase, phospholipase C (PLC), and protein kinase C (PKC). Results implicated all of these pathways in OPN-induced cell migration, the most pronounced effect being seen with PLC and PKC inhibitors. These results suggest that induction of MEC migration by OPN involves a cascade of events including at least two growth factor/receptor pathways and multiple downstream signal transduction pathways. A number of potential targets are thus provided for strategies aimed at blocking the malignancy-promoting effects of OPN.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Adelsman MA, McCarthy JB and Shimizu Y . (1999). Mol. Biol. Cell, 10, 2861–2878.

  • Band V, Zajchowski D, Swisshelm K, Trask D, Kulesa V, Cohen C, Connolly J and Sager R . (1990). Cancer Res., 50, 7351–7357.

  • Bellahcène A and Castronovo V . (1995). Am. J. Pathol., 146, 95–100.

  • Brown LF, Papadopoulos-Sergiou A, Berse B, Manseau EJ, Tognazzi K, Peruzzi CA, Dvorak HF and Senger DR . (1994). Am. J. Pathol., 145, 610–623.

  • Comoglio PM . (1993). EXS., 65, 131–165.

  • Derynck R, Roberts AB, Winkler ME, Chen EY and Goeddel DV . (1984). Cell, 38, 287–297.

  • Donato NJ, Gallick GE, Steck PA and Rosenblum MG . (1989). J. Biol. Chem., 264, 20474–20481.

  • Furger KA, Menon R, Tuck AB, Bramwell VHC and Chambers AF . (2001). Curr. Mol. Med., 1, 621–632 (invited review).

  • Giancotti FG and Ruoslahti E . (1999). Science, 285, 1028–1032.

  • Hirota S, Ito A, Nagoshi J, Takeda M, Kurata A, Takatsuka Y, Kohri K, Nomura S and Kitamura Y . (1995). Lab. Invest., 72, 64–69.

  • Jones PL, Crack J and Rabinovitch M . (1997). J Cell Biol., 139, 279–293.

  • Kassis J, Moellinger J, Lo H, Greenberg NM, Kim HG and Wells A . (1999).Clin. Cancer Res., 5, 2251–2260.

  • Kermorgant S, Aparicio T, Dessirier V, Lewin MJ and Lehy T . (2001). Carcinogenesis, 22, 1035–1042.

  • Lee JW and Juliano RL . (2002). Biochim. Biophys. Acta, 1542, 23–31.

  • Miyamoto S, Teramoto H, Gutkind JS and Yamada K . (1996). J Cell Biol., 135, 1633–1642.

  • Moro L, Dolce L, Cabodi S, Bergatto E, Erba EB, Smeriglio M, Turco E, Retta SF, Giuffrida MG, Venturino M, Godovac-Zimmermann J, Conti A, Schaefer E, Beguinot L, Tacchetti C, Gaggini P, Silengo L, Tarone G and Defilippi P . (2002). J. Biol. Chem., 277, 9405–9414.

  • Murray JC, DeHaven CR and Bell GI . (1986). Nucleic Acids Res., 14, 5117.

  • Price JE, Polyzos A, Zhang RD and Daniels LM . (1990). Cancer Res., 50, 717–721.

  • Price JT, Tiganis T, Agarwal A, Djakiew D and Thompson EW . (1999). Cancer Res., 59, 5475–5478.

  • Qiao H, Saulnier R, Patryzkat A, Rahimi N, Raptis L, Rossiter J, Tremblay E and Elliott B . (2000). Cell Growth Differ., 11, 123–133.

  • Schneller M, Vuori K and Ruoslahti E . (1997). EMBO J., 16, 5600–5607.

  • Schwartz MA . (1997). J. Cell Biol., 139, 575–578.

  • Schwartz MA and Ginsberg MH . (2002). Nature Cell Biol., 4, E65–E68.

  • Senger DR, Peruzzi CA, Gracey CF, Papadopoulos A and Tenen DG . (1988). Cancer Res., 48, 5770–5774.

  • Singhal H, Bautista DS, Tonkin KS, O'Malley FP, Tuck AB, Chambers AF and Harris JF . (1997). Clin. Cancer Res., 3, 605–611.

  • Sodek J, Ganss B and McKee MD . (2000). Crit. Rev. Oral Biol. Med., 11, 279–303.

  • Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G and Bussolino F . (1999). EMBO J., 18, 882–892.

  • Tuck AB, Arsenault DM, O'Malley FP, Hota C, Ling MC, Wilson SM and Chambers AF . (1999). Oncogene, 18, 4237–4246.

  • Tuck AB and Chambers AF . (2001). J. Mammary Gland Biol. Neoplasia, 6, 419–429.

  • Tuck AB, Elliott BE, Hota C, Tremblay E and Chambers AF . (2000). J. Cell. Biochem., 78, 465–475.

  • Tuck AB, O'Malley FP, Singhal H, Harris JF, Tonkin KS, Kerkvliet N, Saad Z, Doig G and Chambers AF . (1998). Int. J. Cancer, 79, 502–508.

  • Tuck AB, Wilson SM and Chambers AF . (1990). Clin. Exp. Metastasis, 8, 417–431.

  • Tuck AB, Wilson SM, Khokha R and Chambers AF . (1991). J. Natl. Cancer Inst., 83, 485–491.

  • Wang R, Kobayashi R and Bishop JM . (1996). Proc. Natl. Acad. Sci., 93, 8425–8430.

  • Wang F, Weaver WM, Petersen OW, Larabell CA, Dedhar S, Briand P, Lupu R and Bissell MJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 14821–14826.

  • Wells A . (1999). Int. J. Biochem. Cell Biol., 31, 637–643.

  • Wells A . (2000). Adv. Cancer Res., 78, 31–101.

  • Xu YH, Ishii S, Clark AJ, Sullivan M, Wilson RK, Ma DP, Roe BA, Merlino GT and Pastan I . (1984). Nature, 309, 806–810.

  • Xuan JW, Hota C and Chambers AF . (1994). J. Cell. Biochem., 54, 247–255.

  • Xuan JW, Hota C, Shigeyama Y, D'Errico JA, Somerman MJ and Chambers AF . (1995). J. Cell. Biochem., 57, 680–690.

Download references

Acknowledgements

This work was supported by a grant from the Canadian Breast Cancer Research Initiative (#012078) and by a ‘Career Development’ Award from the US Army Breast Cancer Research Program (DOD DAMD17-96-1-6075) to Dr Tuck. The content of this article does not necessarily reflect the position or policy of the US government, and no official endorsement should be inferred.

Author information

Authors and Affiliations

  1. Department of Pathology, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada

    Alan B Tuck & Charulata Hota

  2. Department of Oncology, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada

    Alan B Tuck & Ann F Chambers

  3. London Regional Cancer Centre, London, Ontario, Canada

    Alan B Tuck, Charulata Hota, Sylvia M Wilson & Ann F Chambers

Authors
  1. Alan B Tuck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charulata Hota
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sylvia M Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ann F Chambers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan B Tuck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tuck, A., Hota, C., Wilson, S. et al. Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. Oncogene 22, 1198–1205 (2003). https://doi.org/10.1038/sj.onc.1206209

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206209

Keywords

This article is cited by

Search

Advanced search

Quick links