Transforming growth factor-beta1 is the predominant isoform required for breast cancer cell outgrowth in bone.
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.
Mourskaia
A A
AA
Department of Medicine, McGill University, Montreal, Quebec, Canada.
Dong
Z
Z
Ng
S
S
Banville
M
M
Zwaagstra
J C
JC
O'Connor-McCourt
M D
MD
Siegel
P M
PM
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010014:Osteolysis / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D053782:Transforming Growth Factor beta3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II