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Enhanced tenascin-C expression and matrix deposition during Ras/TGF-β-induced progression of mammary tumor cells

Oncogene volume 23, pages 3622–3633 (2004)Cite this article

Abstract

Overexpression of tenascin-C (TN-C) in breast carcinomas has been associated with a migratory or even invasive tumor cell phenotype. The mechanisms regulating expression and matrix deposition of TN-C in normal and cancerous breast tissues are, however, little understood. Here, we demonstrate that mouse mammary epithelial cells (EpH4) transformed by oncogenic Ha-Ras (EpRas) overexpress TN-C, which accumulates in the cytoplasm. When EpRas cells undergo epithelial-mesenchymal transition (EMT) in response to TGFβ1, they secrete TN-C into the culture medium. In EpRas cells undergoing TGFβ1-induced EMT in three-dimensional (3D)-collagen gel cultures, TN-C was deposited into an extracellular matrix (ECM) already containing fibronectin and perlecan. Under less physiological 2D plastic cultures, EpRas cells undergoing EMT failed to deposit TN-C into an (apparently incomplete) ECM. Ras-downstream signaling was dissected by pharmacological inhibitors and effector-specific Ras mutants (V12S35, V12C40), specifically inhibiting or activating ERK/MAPK or PI3K signaling, respectively. We showed that TN-C overexpression required a hyperactive ERK/MAPK-signaling pathway, while elevated PI3K signaling did not enhance TN-C expression. Similarly, tumors induced by cells exhibiting hyperactive ERK/MAPK signaling showed expression of TN-C in the tumor cells themselves, while only endothelial cells expressed TN-C in tumors caused by the V12C40 mutant (incapable of EMT in vivo). Taken together, our data indicate that hyperactive ERK/MAPK signaling causes enhanced expression of TN-C, while its secretion is induced by TGFβ1 and both signals cooperate in TN-C matrix deposition. Importantly, both signals also cooperate to induce EMT in vitro and tumor progression/metastasis in vivo.

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Acknowledgements

This work was supported by grants from an EU TMR network (ERBFMRXCT-980197), the Austrian Research funding agency (FWF; SFB 006/612) and the Austrian Industrial Research Promotion Fund (FFF Project No. 803776). S Maschler received a DOC fellowship of the Austrian Academy of Sciences (No. 20968).

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  1. Hartmut Beug and Gerhard Wirl: These two senior authors contributed equally to this work

Authors and Affiliations

  1. Institute of Molecular Pathology, Dr. Bohrgasse 7, Vienna, 1030, Austria

    Sabine Maschler, Stefan Grunert & Hartmut Beug

  2. Institute of Molecular Biology of the Austrian Academy of Sciences, Salzburg, Austria

    Adriana Danielopol & Gerhard Wirl

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  1. Sabine Maschler
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Correspondence to Hartmut Beug.

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Maschler, S., Grunert, S., Danielopol, A. et al. Enhanced tenascin-C expression and matrix deposition during Ras/TGF-β-induced progression of mammary tumor cells. Oncogene 23, 3622–3633 (2004). https://doi.org/10.1038/sj.onc.1207403

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