title: Autocrine PDGFR signaling promotes mammary cancer metastasis.
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.
authors.affiliation: Research Institute for Molecular Pathology, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Jechlinger
authors.forename: Andreas
authors.initials: A
authors.lastname: Sommer
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.forename: Peter
authors.initials: P
authors.lastname: Seither
authors.forename: Norbert
authors.initials: N
authors.lastname: Kraut
authors.forename: Paola
authors.initials: P
authors.lastname: Capodiecci
authors.forename: Michael
authors.initials: M
authors.lastname: Donovan
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Hartmut
authors.initials: H
authors.lastname: Beug
authors.forename: Stefan
authors.initials: S
authors.lastname: Grünert
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis; D019898:Autocrine Communication; D001549:Benzamides; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D018631:ras Proteins