Abstract
In oestrogen receptor (ER)-positive breast carcinoma cells, 17beta-oestradiol suppresses a dose-dependent induction of cell death by tumour necrosis factor alpha (TNF). The ability of oestrogens to promote cell survival in ER-positive breast carcinoma cells is linked to a coordinate increase in Bcl-2 expression, an effect that is blocked with the pure anti-oestrogen ICI 182,780. The role of Bcl-2 in MCF-7 cell survival was confirmed by stable overexpression of Bcl-2 which resulted in suppression of apoptosis induced by doxorubicin (DOX), paclitaxel (TAX) and TNF as compared to vector-control cells. The pure anti-oestrogen ICI 182,780 in combination with TNF, DOX or TAX potentiated apoptosis in vector-transfected cells. Interestingly, pre-treatment with ICI 182,780 markedly enhanced chemotherapeutic drug- or TNF-induced apoptosis in Bcl-2 expressing cells, an effect that was correlated with ICI 182,780 induced activation of c-Jun N-terminal kinase. Our results suggest that the effects of oestrogens/anti-oestrogens on the regulation of apoptosis may involve coordinate activation of signalling events and Bcl-2 expression.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibiotics, Antineoplastic / administration & dosage
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Antibiotics, Antineoplastic / pharmacology
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Antineoplastic Agents, Phytogenic / administration & dosage
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Cell Survival / drug effects
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Doxorubicin / administration & dosage
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Doxorubicin / pharmacology
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Drug Interactions
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Estradiol / administration & dosage
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Estradiol / analogs & derivatives*
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Estradiol / pharmacology*
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Estrogen Receptor Modulators / administration & dosage
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Estrogen Receptor Modulators / pharmacology
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Female
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Fulvestrant
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Genes, bcl-2
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Humans
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasms, Hormone-Dependent / drug therapy*
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Neoplasms, Hormone-Dependent / genetics
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Neoplasms, Hormone-Dependent / metabolism
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Neoplasms, Hormone-Dependent / pathology*
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Paclitaxel / administration & dosage
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Paclitaxel / pharmacology
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Signal Transduction
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Transfection
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / administration & dosage
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Antibiotics, Antineoplastic
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Antineoplastic Agents, Phytogenic
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Estrogen Receptor Modulators
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Tumor Necrosis Factor-alpha
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Fulvestrant
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Estradiol
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Doxorubicin
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Mitogen-Activated Protein Kinases
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Paclitaxel