Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases

J Clin Invest. 2002 Jun;109(12):1551-9. doi: 10.1172/JCI15234.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Polyomavirus Transforming / genetics
  • Apoptosis*
  • Autocrine Communication
  • Breast / drug effects
  • Breast / pathology
  • Cell Movement
  • Cell Survival
  • Female
  • Genetic Vectors
  • Immunoglobulin Fc Fragments / administration & dosage
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / physiology*
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / genetics
  • Immunoglobulin G / physiology*
  • Lung Neoplasms / secondary*
  • Mammary Neoplasms, Animal / pathology*
  • Mammary Tumor Virus, Mouse
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Neoplasm Metastasis
  • Neovascularization, Pathologic
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / administration & dosage
  • Receptors, Transforming Growth Factor beta / immunology
  • Receptors, Transforming Growth Factor beta / physiology*
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology
  • Signal Transduction*
  • Solubility
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta1
  • Tumor Cells, Cultured

Substances

  • Antigens, Polyomavirus Transforming
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II