Abstract
Transforming growth factor (TGF)-beta signaling is a potent modulator of the invasive and metastatic behavior of breast cancer cells. Indeed, breast tumor responsiveness to TGF-beta is important for the development of osteolytic bone metastases. However, the specific TGF-beta isoforms that promote breast cancer outgrowth in bone is unknown. We demonstrate that expression of a TGF-beta ligand trap, which neutralizes TGF-beta1 and TGF-beta3, 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-beta1 expression within the bone microenvironment of TGF-beta1+/- and TGF-beta1-/- 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-beta1-deficient mice had upregulated expression of all three TGF-beta isoforms. Finally, breast cancer cells expressing the TGF-beta ligand trap showed a pronounced reduction in their ability to form osteolytic lesions when injected into the tibiae of TGF-beta1+/- mice. Thus, our studies show that both host- and tumor-derived TGF-beta expression plays a critical role during the establishment and outgrowth of breast cancer cells in bone.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology*
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Bone Neoplasms / secondary
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Breast Neoplasms / prevention & control
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DNA-Binding Proteins / physiology
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Female
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Humans
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Immunoenzyme Techniques
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Mice
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Mice, Knockout
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Mice, Nude
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Osteolysis / pathology
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Osteolysis / prevention & control*
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Phosphorylation
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Protein Isoforms
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / immunology
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Receptors, Transforming Growth Factor beta / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Smad2 Protein / metabolism
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Transforming Growth Factor beta1 / antagonists & inhibitors
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Transforming Growth Factor beta1 / physiology*
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Transforming Growth Factor beta3 / antagonists & inhibitors
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Transforming Growth Factor beta3 / genetics
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Transforming Growth Factor beta3 / metabolism
Substances
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DNA-Binding Proteins
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Protein Isoforms
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RNA, Messenger
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Rag2 protein, mouse
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Receptors, Transforming Growth Factor beta
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Smad2 Protein
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Smad2 protein, mouse
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Transforming Growth Factor beta1
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Transforming Growth Factor beta3
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II