Autocrine PDGFR signaling promotes mammary cancer metastasis

Martin Jechlinger

Andreas Sommer

Richard Moriggl

Peter Seither

^{Research Institute for Molecular Pathology, Vienna, Austria.}^{Boehringer Ingelheim Pharma KG, Genomics Group, Biberach, Germany.}^{Boehringer Ingelheim Austria GmbH, Department of Lead Discovery, Vienna, Austria.}^{Aureon Laboratories, Yonkers, New York, USA.}^{Memorial Sloan-Kettering Cancer Center, New York, New York, USA.}

Address correspondence to: Hartmut Beug, Research Institute for Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria. Phone: 43-1-79730-883; Fax: 43-1-7987153; E-mail: ta.ca.eivinu.pmi@gueb . Or to: Martin Jechlinger, Memorial Sloan-Kettering Cancer Center, 1225 York Avenue, New York, New York 10021, USA. Phone: (212) 639-6193; Fax: (212) 717-3125; E-mail: gro.ccksm@mnilhcej .

Received 2005 Feb 4; Accepted 2006 Mar 21.

Abstract

Metastasis is the major cause of cancer morbidity, but strategies for direct interference with invasion processes are lacking. Dedifferentiated, late-stage tumor cells secrete multiple factors that represent attractive targets for therapeutic intervention. Here we show that metastatic potential of oncogenic mammary epithelial cells requires an autocrine PDGF/PDGFR loop, which is established as a consequence of TGF-β–induced epithelial-mesenchymal transition (EMT), a faithful in vitro correlate of metastasis. The cooperation of autocrine PDGFR signaling with oncogenic Ras hyperactivates PI3K and is required for survival during EMT. Autocrine PDGFR signaling also contributes to maintenance of EMT, possibly through activation of STAT1 and other distinct pathways. Inhibition of PDGFR signaling interfered with EMT and caused apoptosis in murine and human mammary carcinoma cell lines. Consequently, overexpression of a dominant-negative PDGFR or application of the established cancer drug STI571 interfered with experimental metastasis in mice. Similarly, in mouse mammary tumor virus–Neu (MMTV-Neu) transgenic mice, TGF-β enhanced metastasis of mammary tumors, induced EMT, and elevated PDGFR signaling. Finally, expression of PDGFRα and -β correlated with invasive behavior in human mammary carcinomas. Thus, autocrine PDGFR signaling plays an essential role during cancer progression, suggesting a novel application of STI571 to therapeutically interfere with metastasis.

Abstract

Acknowledgments

We thank K. Politi and C. Summerfield for comments on the manuscript and G. Litos and I. Tamir for expert technical assistance, the Department of Biological Sciences, University of Iowa, for anti-cytokeratin antibodies (TROMA-I), and G. Loeber, Boehringer Ingelheim–Austria, for supplying us with huPDGFR/FDCP-1 cells and a specific PDGFR tyrosine kinase inhibitor. This work was supported by grants from a European Union Training and Mobility of Researchers Programme (ERBFMRXCT-980197), the Austrian Research funding agency (FWF; SFB 006/612 and SFB F28), and the Austrian Industrial Research Promotion Fund (FFF project no. 803776).

Acknowledgments

Footnotes

Nonstandard abbreviations used: dnP, dominant-negative PDGFR; EMT, epithelial-mesenchymal transition; EpRas cell, Ras-transformed EpH4 cell; FDCP-1, factor-dependent continuous cell line, Paterson Laboratories 1; MMTV, mouse mammary tumor virus; RTK, receptor tyrosine kinase; TGF-βRII, TGF-β receptor II.

Conflict of interest: The authors have declared that no conflict of interest exists.

Citation for this article:J. Clin. Invest.116:1561–1570 (2006). doi:10.1172/JCI24652.

Martin Jechlinger’s present address is: Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Richard Moriggl’s present address is: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

Stefan Grünert’s present address is: Children’s Cancer Research Institute, Vienna, Austria.

Hartmut Beug and Stefan Grünert contributed equally to this work.

Footnotes

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