title: Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways.
abstract: Transforming growth factor (TGF)-beta 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-beta, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-beta 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-beta can signal through both Smad and mitogen-activated protein (MAP) kinase pathways. Stable transfection of wild-type Smad2, Smad3, or Smad4 increased TGF-beta-stimulated PTHrP secretion, whereas dominant-negative Smad2, Smad3, or Smad4 only partially reduced TGF-beta-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-beta-stimulated PTHrP production. The combination of Smad dominant-negative blockade and p38 MAP kinase inhibition resulted in complete inhibition of TGF-beta-stimulated PTHrP production. Furthermore, TGF-beta 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-beta and may provide a new molecular target for anti-osteolytic therapy.
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245-3217, USA.
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Kakonen
authors.forename: Katri S
authors.initials: KS
authors.lastname: Selander
authors.forename: John M
authors.initials: JM
authors.lastname: Chirgwin
authors.forename: Juan Juan
authors.initials: JJ
authors.lastname: Yin
authors.forename: Suzanne
authors.initials: S
authors.lastname: Burns
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Rankin
authors.forename: Barry G
authors.initials: BG
authors.lastname: Grubbs
authors.forename: Mark
authors.initials: M
authors.lastname: Dallas
authors.forename: Yong
authors.initials: Y
authors.lastname: Cui
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
mesh_terms: D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D044162:Parathyroid Hormone-Related Protein; D011480:Protease Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011480:Protease Inhibitors; D011506:Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases