1. Autocrine PDGFR signaling promotes mammary cancer metastasis.
- Author
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Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, Donovan M, Cordon-Cardo C, Beug H, and Grünert S
- Subjects
- Animals, Antineoplastic Agents metabolism, Apoptosis, Benzamides, Cell Differentiation physiology, Cell Line, Tumor, Enzyme Activation, Epithelial Cells cytology, Epithelial Cells physiology, Female, Humans, Imatinib Mesylate, Mammary Tumor Virus, Mouse genetics, Mammary Tumor Virus, Mouse metabolism, Mesoderm physiology, Mice, Mice, Nude, Mice, Transgenic, Phosphatidylinositol 3-Kinases metabolism, Piperazines metabolism, Protein Kinase Inhibitors metabolism, Pyrimidines metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, ras Proteins metabolism, Autocrine Communication, Breast Neoplasms metabolism, Breast Neoplasms pathology, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Neoplasm Metastasis, Receptor, Platelet-Derived Growth Factor alpha metabolism, Receptor, Platelet-Derived Growth Factor beta metabolism, Signal Transduction physiology
- 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-beta-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-beta enhanced metastasis of mammary tumors, induced EMT, and elevated PDGFR signaling. Finally, expression of PDGFRalpha and -beta 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.
- Published
- 2006
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