title: Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases.
abstract: TGF-betas are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-beta interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-beta type II receptor fusion protein (Fc:TbetaRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TbetaRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TbetaRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TbetaRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TbetaRII. Therefore, blockade of TGF-beta signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 27232, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Muraoka
authors.forename: Nancy
authors.initials: N
authors.lastname: Dumont
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Ritter
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Dugger
authors.forename: Dana M
authors.initials: DM
authors.lastname: Brantley
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: Evangeline
authors.initials: E
authors.lastname: Easterly
authors.forename: L Renee
authors.initials: LR
authors.lastname: Roebuck
authors.forename: Sarah
authors.initials: S
authors.lastname: Ryan
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Gotwals
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D017209:Apoptosis; D019898:Autocrine Communication; D001940:Breast / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement; D002470:Cell Survival; D005260:Female; D005822:Genetic Vectors; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000556:secondary*; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage / Q000276:immunology / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
chemical_list: D000952:Antigens, Polyomavirus Transforming; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II