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Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway

Oncogene volume 21, pages 5148–5159 (2002)Cite this article

Abstract

Carcinogenesis by oncogenic Ras and Her-2 involves enhanced proliferation of epithelial cells in vivo. However, hyperproliferation induced by these oncogenes, or their downstream pathways in vitro has mainly been studied in cultured, fibroblastic cell lines. Here, we demonstrate that oncogenic Ha-Ras or constitutively active Her-2 cause increased proliferation and cyclin D1 upregulation in fully polarized, mammary epithelial cells (EpH4), if cultivated as organotypic structures in three-dimensional collagen/matrigel matrices. Under standard culture conditions, however, these oncogenes failed to induce hyperproliferation. Using both specific low molecular weight inhibitors and Ras-effector–specific mutants, we dissected signaling pathways downstream of oncogenic Ras (PI3K, Mek1/MAPK) with respect to (i) hyperproliferation in collagen gels and tumorigenesis in mice and (ii) epithelial/mesenchymal transition (EMT). We show that the Ras-activated PI3K pathway is required to induce rapid tumor growth and enhanced proliferation of EpH4 cells in collagen gels, but fails to cause EMT in vitro and in vivo. On the other hand, Ras-dependent activation of the Mek1/MAPK pathway in EpH4 cells (previously shown to cause EMT and metastasis) did not induce hyperproliferation in collagen gels and caused only slow tumor growth. Our data thus indicate that Ras-dependent signaling through the PI3K- and MAPK pathways fulfil distinct, but complementary functions during carcinogenesis.

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Acknowledgements

The authors thank M Baccarini for critically reading the manuscript and useful comments and Drs G Christofori and R Foisner (all VBC, Vienna) for stimulating discussions, Dr R Kemler for his gift of anti-E-cadherin antibodies and Martin Jechlinger for vimentin probes and developing the in-gel apoptosis assays. E Janda, S Grünert and H Beug were supported by grants from an EU TMR network (ERBFMRXCT-980197), from the Austrian Research funding agency (FWF; SFB 006/612) and the Austrian Industrial Research Promotion Fund (FFF, project No 803776).

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Authors and Affiliations

  1. Institute of Molecular Pathology, Dr. Bohr-Gasse 7, Vienna, A-1030, Austria

    Elzbieta Janda, Gabi Litos, Stefan Grünert & Hartmut Beug

  2. Signal Transduction Laboratories, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Julian Downward

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  1. Elzbieta Janda
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Correspondence to Hartmut Beug.

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Janda, E., Litos, G., Grünert, S. et al. Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway. Oncogene 21, 5148–5159 (2002). https://doi.org/10.1038/sj.onc.1205661

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