TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development

J Clin Invest. 1999 Jan;103(2):197-206. doi: 10.1172/JCI3523.

Abstract

Breast cancer frequently metastasizes to the skeleton, and the associated bone destruction is mediated by the osteoclast. Growth factors, including transforming growth factor-beta (TGF-beta), released from bone matrix by the action of osteoclasts, may foster metastatic growth. Because TGF-beta inhibits growth of epithelial cells, and carcinoma cells are often defective in TGF-beta responses, any role of TGF-beta in metastasis is likely to be mediated by effects on the surrounding normal tissue. However, we present evidence that TGF-beta promotes breast cancer metastasis by acting directly on the tumor cells. Expression of a dominant-negative mutant (TbetaRIIDeltacyt) of the TGF-beta type II receptor rendered the human breast cancer cell line MDA-MB-231 unresponsive to TGF-beta. In a murine model of bone metastases, expression of TbetaRIIDeltacyt by MDA-MB-231 resulted in less bone destruction, less tumor with fewer associated osteoclasts, and prolonged survival compared with controls. Reversal of the dominant-negative signaling blockade by expression of a constitutively active TGF-beta type I receptor in the breast cancer cells increased tumor production of parathyroid hormone-related protein (PTHrP), enhanced osteolytic bone metastasis, and decreased survival. Transfection of MDA-MB-231 cells that expressed the dominant-negative TbetaRIIDeltacyt with the cDNA for PTHrP resulted in constitutive tumor PTHrP production and accelerated bone metastases. These data demonstrate an important role for TGF-beta in the development of breast cancer metastasis to bone, via the TGF-beta receptor-mediated signaling pathway in tumor cells, and suggest that the bone destruction is mediated by PTHrP.

Publication types

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

MeSH terms

  • Animals
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / secondary
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cross-Linking Reagents / metabolism
  • Disease Models, Animal
  • Extremities / pathology
  • Growth Substances / pharmacology
  • Mice
  • Mutation
  • Neoplasms, Experimental / metabolism
  • Osteoclasts / metabolism*
  • Osteoclasts / pathology
  • Parathyroid Hormone-Related Protein
  • Protein-Serine-Threonine Kinases
  • Proteins / metabolism*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • Transfection / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tumor Cells, Cultured

Substances

  • Cross-Linking Reagents
  • Growth Substances
  • Parathyroid Hormone-Related Protein
  • Proteins
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II