Autocrine TGFbeta supports growth and survival of human breast cancer MDA-MB-231 cells.
Using a cell model system established by ectopic expression of a soluble TGFbeta type III receptor (sRIII) containing the whole extracellular domain of the type III receptor in human breast cancer MDA-MB-231 cells, we observed that the expression of sRIII antagonized TGFbeta activity and inhibited both anchorage-dependent and anchorage-independent cell growth. Further studies revealed that sRIII expression induced apoptosis both in vitro and in vivo. Treatment with TGFbeta neutralizing antibodies or a recombinant human sRIII also induced apoptosis in the MDA-MB-231 parental cells, suggesting that the increased apoptosis after sRIII expression was specifically due to antagonization of autocrine TGFbeta signaling. Western blotting showed that sRIII clones had a higher PTEN expression level than the control cells did. Treatment with TGFbeta(1) decreased PTEN and inhibited apoptosis in sRIII cells to a level similar to that in the control cells. sRIII clones also showed a lower level of phosphorylated-Akt than the control cells, consistent with the inhibitory activity of PTEN on Akt activation. Treatment with LY294002, a specific inhibitor of Akt activator, phosphatidylinositol 3-kinase, also induced apoptosis in a dose dependent manner in the control cells. Our results suggest that autocrine TGFbeta signaling is necessary for the growth and survival of MDA-MB-231 cells.
Lei
Xiufen
X
Department of Cellular & Structural Biology, The University of Texas Health Science Center, San Antonio, Texas, TX 78229, USA.
Bandyopadhyay
Abhik
A
Le
Thy
T
Sun
LuZhe
L
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C071736:betaglycan; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt