Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases.
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.
Muraoka
Rebecca S
RS
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 27232, USA.
Dumont
Nancy
N
Ritter
Christoph A
CA
Dugger
Teresa C
TC
Brantley
Dana M
DM
Chen
Jin
J
Easterly
Evangeline
E
Roebuck
L Renee
LR
Ryan
Sarah
S
Gotwals
Philip J
PJ
Koteliansky
Victor
V
Arteaga
Carlos L
CL
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
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