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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.

Pubmed ID: 12070302

Authors

  • Muraoka RS
  • Dumont N
  • Ritter CA
  • Dugger TC
  • Brantley DM
  • Chen J
  • Easterly E
  • Roebuck LR
  • Ryan S
  • Gotwals PJ
  • Koteliansky V
  • Arteaga CL

Journal

The Journal of clinical investigation

Publication Data

June 18, 2002

Associated Grants

  • Agency: NCI NIH HHS, Id: CA68485
  • Agency: NCI NIH HHS, Id: R01 CA-62212
  • Agency: NCI NIH HHS, Id: T32 CA-09592

Mesh Terms

  • Animals
  • Antigens, Polyomavirus Transforming
  • Apoptosis
  • Autocrine Communication
  • Breast
  • Cell Movement
  • Cell Survival
  • Female
  • Genetic Vectors
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Lung Neoplasms
  • Mammary Neoplasms, Animal
  • Mammary Tumor Virus, Mouse
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Neoplasm Metastasis
  • Neovascularization, Pathologic
  • Protein-Serine-Threonine Kinases
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Solubility
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Tumor Cells, Cultured