Interactions between IGF-I, estrogen receptor-α (ERα), and ERβ in regulating growth/apoptosis of MCF-7 human breast cancer cells.
Understanding of the interactions between estradiol (E₂) and IGF-I is still incomplete. Cell lines derived from the MCF-7 breast cancer cells were generated with suppressed expression of the IGF-I receptor (IGF-IR), termed IGF-IR.low cells, by stable transfection using small interfering RNA (siRNA) expression vector. Vector for control cells carried sequence generating noninterfering RNA. Concomitant with reduction in the IGF-IR levels, the IGF-IR.low cells also showed a reduction in estrogen receptor α (ERα) and progesterone receptor expressions, and an elevation in the expression of ERβ. The number of the IGF-IR.low cells was reduced in response to IGF-I and human GH plus epidermal growth factor, but E₂ did not cause an increase in the number of the IGF-IR.low cells compared to controls. The proliferation rate of IGF-IR.low cells was only reduced in response to E₂ compared to controls, whereas their basal and hormone-stimulated apoptosis rate was increased. Phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was increased in the IGF-IR.low cells after treatment with E₂, without affecting control cells. Furthermore, phosphorylation of the tumor suppressor protein p53 was elevated in the IGF-IR.low cells compared to the controls. In conclusion, suppressing IGF-IR expression decreased the level of ERα but increased the level of ERβ. Overall growth rate of the IGF-IR.low cells was reduced mostly through an increase in apoptosis without affecting proliferation substantially. We hypothesize that a decreased ERα:ERβ ratio triggered a rapid phosphorylation of p38 MAPK, which in turn phosphorylated the p53 tumor suppressor and accelerated apoptosis rate.
Mendoza
Rhone A
RA
Department of Biomedical Sciences, Center of Excellence in Cancer Research, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine, 5001 El Paso Drive, El Paso, Texas 79905, USA.
Enriquez
Marlene I
MI
Mejia
Sylvia M
SM
Moody
Emily E
EE
Thordarson
Gudmundur
G
D000704:Analysis of Variance; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D048051:p38 Mitogen-Activated Protein Kinases