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:

Expression of activated M-Ras in a murine mammary epithelial cell line induces epithelial–mesenchymal transition and tumorigenesis

Oncogene volume 23, pages 1187–1196 (2004)Cite this article

An Erratum to this article was published on 18 November 2004

Abstract

The expression of activated mutants of M-Ras (G22V or Q71L), but not wild-type M-Ras, in a murine mammary epithelial cell line, scp2, resulted in epithelial–mesenchymal transition (EMT) and oncogenic transformation. Cells expressing constitutively active M-Ras continued to grow in the absence of serum and exhibited a loss of the epithelial markers cytokeratin, E-cadherin and β-catenin, together with a gain of the mesenchymal marker vimentin, a loss of contact inhibition in monolayer growth and a gain of the capacity for anchorage-independent growth. Moreover, unlike the parental cells, they failed to form differentiated mammospheres on Matrigel and instead formed branched networks of cells that grew and invaded the Matrigel. The expression of activated p21 Ras (G12V H-Ras or Q61K N-Ras) also resulted in EMT and tumorigenesis, although there was evidence that expression of higher levels was toxic. Tumors derived from scp2 cells expressing activated M-Ras exhibited activation of Akt and of ERK. The levels of expression of Q71L M-Ras and G12V H-Ras required for tumorigenesis were comparable, although higher levels of the weaker G22V M-Ras mutant were selected for in vivo. These data indicate that the expression of activated mutants of M-Ras was sufficient for oncogenic transformation of a murine mammary epithelial cell line.

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
Figure 8

Similar content being viewed by others

References

  • Barker KT and Crompton MR . (1998). Br. J. Cancer, 78, 296–300.

  • Boon K, Osorio EC, Greenhut SF, Schaefer CF, Shoemaker J, Polyak K, Morin PJ, Buetow KH, Strausberg RL, De Souza SJ and Riggins GJ . (2002). Proc. Natl. Acad. Sci. USA, 99, 11287–11292.

  • Bos JL . (1988). Mutat. Res., 195, 255–271.

  • Bos JL . (1989). (Published erratum appears in Cancer Res. (1990) Feb 15; 50(4): 1352). Cancer Res., 49, 4682–4689.

  • Chan AM, Miki T, Meyers KA and Aaronson SA . (1994). Proc. Natl. Acad. Sci. USA, 91, 7558–7562.

  • Clark GJ, Kinch MS, Gilmer TM, Burridge K and Der CJ . (1996). Oncogene, 12, 169–176.

  • Cox AD, Brtva TR, Lowe DG and Der CJ . (1994). Oncogene, 9, 3281–3288.

  • Crissman HA, Darzynkiewicz Z, Tobey RA and Steinkamp JA . (1985). Science, 228, 1321–1324.

  • Danielson KG, Oborn CJ, Durban EM, Butel JS and Medina D . (1984). Proc. Natl. Acad. Sci. USA, 81, 3756–3760.

  • Desprez P, Roskelley C, Campisi J and Bissell MJ . (1993). Mol. Cell. Differ., 1, 99–110.

  • Ehrhardt A, Ehrhardt G, Guo X and Schrader J . (2002). Exp. Hematol., 30, 1089.

  • Ehrhardt GR, Korherr C, Wieler JS, Knaus M and Schrader JW . (2001). Oncogene, 20, 188–197.

  • Ehrhardt GR, Leslie KB, Lee F, Wieler JS and Schrader JW . (1999). Blood, 94, 2433–2444.

  • Fanton CP, McMahon M and Pieper RO . (2001). J. Biol. Chem., 276, 18871–18877.

  • Gao X, Satoh T, Liao Y, Song C, Hu CD, Kariya Ki K and Kataoka T . (2001). J. Biol. Chem., 276, 42219–42225.

  • Grill B and Schrader JW . (2002). Blood, 100, 3183–3192.

  • Hamad NM, Elconin JH, Karnoub AE, Bai W, Rich JN, Abraham RT, Der CJ and Counter CM . (2002). Genes Dev., 16, 2045–2057.

  • Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H and Grunert S . (2002a). J. Cell. Biol., 156, 299–314.

  • Janda E, Litos G, Grunert S, Downward J and Beug H . (2002b). Oncogene, 21, 5148–5159.

  • Kimmelman A, Tolkacheva T, Lorenzi MV, Osada M and Chan AM . (1997). Oncogene, 15, 2675–2685.

  • Kimmelman AC, Osada M and Chan AM . (2000). Oncogene, 19, 2014–2022.

  • Lochter A, Srebrow A, Sympson CJ, Terracio N, Werb Z and Bissell MJ . (1997). J. Biol. Chem., 272, 5007–5015.

  • Louahed J, Grasso L, De Smet C, Van Roost E, Wildmann C, Nicolaides NC, Levitt RC and Renauld JC . (1999). Blood, 94, 1701–1710.

  • Lowe DG, Capon DJ, Delwart E, Sakaguchi AY, Naylor SL and Goeddel DV . (1987). Cell, 48, 137–146.

  • Macmanus MP, Elder GE, Abram WP and Bridges JM . (1990). Exp. Hematol., 18, 848–852.

  • Matsumoto K, Asano T and Endo T . (1997). Oncogene, 15, 2409–2417.

  • Miyakis S, Sourvinos G and Spandidos DA . (1998). Biochem. Biophys. Res. Commun., 251, 609–612.

  • Naviaux RK, Costanzi E, Haas M and Verma IM . (1996). J. Virol., 70, 5701–5705.

  • Noda M . (1993). Biochim. Biophys. Acta, 1155, 97–109.

  • Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K and Matsuda M . (2000). J. Biol. Chem., 275, 20020–20026.

  • Perou CM, Sorlie T, Eisen MB, van de RM, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO and Botstein D . (2000). Nature, 406, 747–752.

  • Pritchard C and McMahon M . (1997). Nat. Genet., 16, 214–215.

  • Pruitt K, Pruitt WM, Bilter GK, Westwick JK and Der CJ . (2002). J. Biol. Chem., 277, 31808–31817.

  • Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ and Bi C . (1999). J. Biol. Chem., 274, 23850–23857.

  • Quilliam LA, Rebhun JF, Zong H and Castro AF . (2001). Methods Enzymol., 333, 187–202.

  • Rebhun JF, Castro AF and Quilliam LA . (2000). J. Biol. Chem., 275, 34901–34908.

  • Roskelley CD, Wu C and Somasiri AM . (2000). Methods Mol. Biol., 136, 27–38.

  • Tombes RM, Auer KL, Mikkelsen R, Valerie K, Wymann MP, Marshall CJ, McMahon M and Dent P . (1998). Biochem. J., 330 (Part 3), 1451–1460.

  • Tremblay PJ, Pothier F, Hoang T, Tremblay G, Brownstein S, Liszauer A and Jolicoeur P . (1989). Mol. Cell. Biol., 9, 854–859.

  • Urano T, Emkey R and Feig LA . (1996). EMBO J., 15, 810–816.

  • Woods D, Parry D, Cherwinski H, Bosch E, Lees E and McMahon M . (1997). Mol. Cell. Biol., 17, 5598–5611.

Download references

Acknowledgements

We thank Dr Goetz Ehrhardt for critical discussions and Andy Johnson for assistance with FACS analysis. This work was supported by grants from the Canadian Breast Cancer Research Initiative and the Canadian Institutes of Health Research.

Author information

Authors and Affiliations

  1. The Biomedical Research Centre, 2222, Health Sciences Mall, University of British Columbia, Vancouver, V6T 1Z3, BC, Canada

    Katherine R Ward, Kai-Xiu Zhang & John W Schrader

  2. Department of Anatomy and Cell Biology, University of British Columbia, Vancouver, BC, Canada

    Aruna M Somasiri & Calvin D Roskelley

Authors
  1. Katherine R Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai-Xiu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aruna M Somasiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Calvin D Roskelley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John W Schrader
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John W Schrader.

Additional information

Websites referenced:

http://cgap.nci.nih.gov/Genes/GeneInfo?ORG=Hs&CID=349227

http://cgap.nci.nih.gov/SAGE/Viewer?TAG=TCGGGTTTAC&CELL=0

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ward, K., Zhang, KX., Somasiri, A. et al. Expression of activated M-Ras in a murine mammary epithelial cell line induces epithelial–mesenchymal transition and tumorigenesis. Oncogene 23, 1187–1196 (2004). https://doi.org/10.1038/sj.onc.1207226

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207226

Keywords

This article is cited by

Search

Advanced search

Quick links