Mechanisms of 4-hydroxytamoxifen anti-growth factor activity in breast cancer cells: alterations of growth factor receptor binding sites and tyrosine kinase activity.
We previously demonstrated that antiestrogen 4-hydroxytamoxifen (OH-Tam) blocks the mitogenic activity of growth factors in breast cancer. We now investigate this mechanism by evaluating how OH-Tam affects growth factor binding and receptor tyrosine kinase activity. We show here that OH-Tam has an opposite effect on epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) binding in estrogen receptor (ER) positive cells. A decrease in IGF-1 binding sites may explain the reduced IGF-I mitogenic effect, whereas an increase in high affinity EGF binding associated with a decrease in in vitro receptor autophosphorylation rather favors the possibility of an alteration in EGF receptor tyrosine kinase activity. We conclude that OH-Tam may prevent growth factor action in ER+ cells both by modulating the concentration of growth factor binding sites and by altering growth factor receptor functionality.
Freiss
G
G
INSERM Unit 148, Montpellier, France.
Rochefort
H
H
Vignon
F
F
D001943:Breast Neoplasms / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases