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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 RIS Download

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

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA062212
  • Agency: NCI NIH HHS, Id: R01 CA-62212
  • Agency: NCI NIH HHS, Id: T32 CA-09592
  • Agency: NCI NIH HHS, Id: P30 CA068485
  • Agency: NCI NIH HHS, Id: T32 CA009592
  • Agency: NCI NIH HHS, Id: CA68485

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