title: Invasion and metastasis of a mammary tumor involves TGF-beta signaling.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Arizona, Tucson 85724, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: McEarchern
authors.forename: J J
authors.initials: JJ
authors.lastname: Kobie
authors.forename: V
authors.initials: V
authors.lastname: Mack
authors.forename: R S
authors.initials: RS
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Meade-Tollin
authors.forename: C L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: N
authors.initials: N
authors.lastname: Dumont
authors.forename: D
authors.initials: D
authors.lastname: Besselsen
authors.forename: E
authors.initials: E
authors.lastname: Seftor
authors.forename: M J
authors.initials: MJ
authors.lastname: Hendrix
authors.forename: E
authors.initials: E
authors.lastname: Katsanis
authors.forename: E T
authors.initials: ET
authors.lastname: Akporiaye
mesh_terms: 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
chemical_list: 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