Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

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DOIResolve DOI: http://doi.org/10.1038/onc.2008.454
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TypeArticle
Journal titleOncogene
Volume28
Issue7
Pages10051015; # of pages: 11
SubjectAnimal; Animals; antagonists & inhibitors; Bone Neoplasms; Breast Neoplasms; Cells; DNA-Binding Proteins; Female; genetics; genome; Humans; Immunoenzyme Techniques; immunology; metabolism; Mice; Mice,Knockout; Mice,Nude; Osteolysis; pathology; pha; Phosphorylation; physiology; prevention & control; Protein; Protein-Serine-Threonine Kinases; Protein Isoforms; Proteins; Receptors,Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; Rna; RNA,Messenger; secondary; Smad2 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta3; TGF-β isoforms; breast cancer; ligand trap; bone microenvironment
AbstractTransforming growth factor (TGF)-β signaling is a potent modulator of the invasive and metastatic behavior of breast cancer cells. Indeed, breast tumor responsiveness to TGF-β is important for the development of osteolytic bone metastases. However, the specific TGF-β isoforms that promote breast cancer outgrowth in bone is unknown. We demonstrate that expression of a TGF-β ligand trap, which neutralizes TGF-β1 and TGF-β3, in MDA-MB-231 breast cancer cells diminished their outgrowth in bone and reduced the severity of osteolytic lesion formation when compared with controls. We further show that a reduction or loss of TGF-β1 expression within the bone microenvironment of TGF-β1+/- and TGF-β1-/- mice significantly reduced the incidence of breast tumor outgrowth compared with wild-type animals. Interestingly, those tumors capable of growing within the tibiae of TGF-β1- deficient mice had upregulated expression of all three TGF-β isoforms. Finally, breast cancer cells expressing the TGF-β ligand trap showed a pronounced reduction in their ability to form osteolytic lesions when injected into the tibiae of TGF-b1þ +/- mice. Thus, our studies show that both host- and tumor-derived TGF-β expression plays a critical role during the establishment and outgrowth of breast cancer cells in bone.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada; NRC Biotechnology Research Institute
Peer reviewedNo
NRC number49582
NPARC number12919050
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Record identifiera5949b03-a910-4b00-923b-5b8e78e13282
Record created2009-11-10
Record modified2016-05-09
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