Invasion and metastasis of a mammary tumor involves TGF-beta signaling.
Several studies have correlated escape from TGF-beta-mediated cell cycle arrest with the tumorigenic phenotype. Most often, this escape from growth control has been linked to dysfunctional TGF-beta receptors or defects in the TGF-beta-mediated SMAD signaling pathway. In this report, we found that highly metastatic 4T1 mammary carcinoma cells express functional TGF-beta receptors capable of initiating SMAD-mediated transcription, yet are not growth inhibited by TGF-beta1. We further observed that TGF-beta directly contributes to the metastatic behavior of this cell line. Exposure to TGF-beta caused 4T1 cells to undergo morphological changes associated with the metastatic phenotype and invade more readily through collagen coated matrices. Furthermore, expression of a dominant negative truncated type II receptor diminished TGF-beta signaling and significantly restricted the ability of 4T1 cells to establish distant metastases. Our results suggest that regardless of 4T1 resistance to TGF-beta-mediated growth inhibition, TGF-beta signaling is required for tumor invasion and metastases formation.
McEarchern
J A
JA
Department of Microbiology and Immunology, University of Arizona, Tucson 85724, USA.
Kobie
J J
JJ
Mack
V
V
Wu
R S
RS
Meade-Tollin
L
L
Arteaga
C L
CL
Dumont
N
N
Besselsen
D
D
Seftor
E
E
Hendrix
M J
MJ
Katsanis
E
E
Akporiaye
E T
ET
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D005799:Genes, Dominant; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen