Transforming growth factor-β stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways

Sanna Maria Käkönen, Katri S. Selander, John M. Chirgwin, Juan Juan Yin, Suzanne Burns, Wayne A. Rankin, Barry G. Grubbs, Mark Dallas, Yong Cui, Theresa A. Guise

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197 Scopus citations

Abstract

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 antibodytreated 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.

Original languageEnglish (US)
Pages (from-to)24571-24578
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number27
DOIs
StatePublished - Jul 5 2002

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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