Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis.
The influence of transforming growth factor beta (TGF-beta) signaling on Neu-induced mammary tumorigenesis and metastasis was examined with transgenic mouse models. We generated mice expressing an activated TGF-beta type I receptor or dominant negative TGF-beta type II receptor under control of the mouse mammary tumor virus promoter. When crossed with mice expressing activated forms of the Neu receptor tyrosine kinase that selectively couple to the Grb2 or Shc signaling pathways the activated type I receptor increased the latency of mammary tumor formation but also enhanced the frequency of extravascular lung metastasis. Conversely, expression of the dominant negative type II receptor decreased the latency of Neu-induced mammary tumor formation while significantly reducing the incidence of extravascular lung metastases. These observations argue that TGF-beta can promote the formation of lung metastases while impairing Neu-induced tumor growth and suggest that extravasation of breast cancer cells from pulmonary vessels is a point of action of TGF-beta in the metastatic process.
Siegel
Peter M
PM
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Shu
Weiping
W
Cardiff
Robert D
RD
Muller
William J
WJ
Massagué
Joan
J
D030201:Activin Receptors, Type I / Q000235:genetics / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017209:Apoptosis; D029721:Drosophila Proteins; D005260:Female; D051380:GRB2 Adaptor Protein; D005799:Genes, Dominant; D018734:Genes, erbB-2; D006801:Humans; D007774:Lactation; D008025:Ligases / Q000037:antagonists & inhibitors* / Q000502:physiology; D008175:Lung Neoplasms / Q000209:etiology / Q000556:secondary*; D008321:Mammary Glands, Animal / Q000254:growth & development; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D008940:Mitotic Index; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D029721:Drosophila Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D018125:Receptors, Transforming Growth Factor beta; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016212:Transforming Growth Factor beta; D044767:Ubiquitin-Protein Ligases; C071006:neur protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D008025:Ligases