Mechanism of estrogen-induced apoptosis in breast cancer cells: role of the NF-kappaB signaling pathway.
The ability of sex steroid hormones to up-regulate the apoptotic signaling proteins is well documented; however, the apoptotic potential of sex hormones is not remarkable and fully compensated by their growth stimulatory action to target cells. In the present study using the long-term cultivation of estrogen-dependent MCF-7 breast cancer cells in steroid-free medium, we have established a cell subline, designed as MCF-7/LS, which was characterized by the resistance to growth stimulatory estradiol action and hypersensitivity to estrogen-induced apoptosis. We have demonstrated that estrogen treatment of the cells does not influence on the level of TNF-R1 or Fas, but dramatically decreases the transcriptional activity of NF-kappaB. Importantly, the MCF-7/LS cells, which are insensitive to growth stimulatory estrogen action, retain the ability to decrease in the NF-kappaB activity in response to estrogen stimulus. Furthermore, the significant increase in the basal (in the absence of ligand) estrogen receptor (ER)-dependent transcriptional activity in the MCF-7/LS cells was revealed and reciprocal transcriptional antagonism between ER and NF-kappaB was demonstrated. Finally, we proved the possible involvement of phosphatidylinositol-3 kinase (PI3K) in the ligand-independent ER activation. In general, the results presented suggest that long-term growth of MCF-7 breast cancer cells in steroid-free medium is accompanied with the increase in the basal ER-dependent transcriptional activity as well as the maintenance of the negative regulatory loop ER-NF-kappaB. The latter may be considered as one of the factors resulting in a disbalance between pro- and anti-apoptotic pathways and enhancement in estrogen apoptotic action in the cells.
Lobanova
Yu S
YS
Institute of Carcinogenesis, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia.
Scherbakov
A M
AM
Shatskaya
V A
VA
Krasil'nikov
M A
MA
D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011869:Radioligand Assay; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D004967:Estrogens; D008565:Membrane Proteins; D016328:NF-kappa B; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D004958:Estradiol; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase