Transforming Growth Factor-β Stimulates Parathyroid Hormone-related Protein and Osteolytic Metastases via Smad and Mitogen-activated Protein Kinase Signaling Pathways

Transforming growth factor (TGF)-β promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-β, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitut...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-07, Vol.277 (27), p.24571-24578
Main Authors: Käkönen, Sanna-Maria, Selander, Katri S., Chirgwin, John M., Yin, Juan Juan, Burns, Suzanne, Rankin, Wayne A., Grubbs, Barry G., Dallas, Mark, Cui, Yong, Guise, Theresa A.
Format: Article
Language:English
Subjects:
Bone Neoplasms - secondary
Breast Neoplasms
DNA-Binding Proteins - metabolism
Female
Humans
MAP Kinase Signaling System - physiology
Mitogen-Activated Protein Kinases - metabolism
Neoplasm Metastasis
Parathyroid Hormone-Related Protein
Protease Inhibitors - pharmacology
Proteins - pharmacology
Proteins - physiology
Signal Transduction - physiology
Smad Proteins
Trans-Activators - metabolism
Transforming Growth Factor beta - physiology
Tumor Cells, Cultured
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Summary:Transforming growth factor (TGF)-β promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-β, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-β type I receptor. Treatment of the mice with a PTHrP-neutralizing antibody greatly decreased osteolytic bone metastases. There were fewer osteoclasts and significantly decreased tumor area in the antibody-treated mice. TGF-β can signal through both Smad and mitogen-activated protein (MAP) kinase pathways. Stable transfection of wild-type Smad2, Smad3, or Smad4 increased TGF-β-stimulated PTHrP secretion, whereas dominant-negative Smad2, Smad3, or Smad4 only partially reduced TGF-β-stimulated PTHrP secretion. When the cells were treated with a variety of protein kinases inhibitors, only specific inhibitors of the p38 MAP kinase pathway significantly reduced both basal and TGF-β-stimulated PTHrP production. The combination of Smad dominant-negative blockade and p38 MAP kinase inhibition resulted in complete inhibition of TGF-β-stimulated PTHrP production. Furthermore, TGF-β treatment of MDA-MB-231 cells resulted in a rapid phosphorylation of p38 MAP kinase. Thus, the p38 MAP kinase pathway appears to be a major component of Smad-independent signaling by TGF-β and may provide a new molecular target for anti-osteolytic therapy.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M202561200