Abstract
Resistance to endocrine therapies remains a major problem in the management of estrogen receptor-alpha (ER)-positive breast cancer. We show that inhibition of NF-kappaB (p65/RELA), either by overexpression of a mutant IkappaB (IkappaBSR) or a small-molecule inhibitor of NF-kappaB (parthenolide; IC(50)=500 nM in tamoxifen-resistant cells), synergistically restores sensitivity to 4-hydroxytamoxifen (4HT) in resistant MCF7/RR and MCF7/LCC9 cells and further sensitizes MCF-7 and MCF7/LCC1 control cells to 4HT. These effects are independent of changes in either cell cycle distribution or in the level of autophagy measured by inhibition of p62/SQSTM1 expression and cleavage of LC3. NF-kappaB inhibition restores the ability of 4HT to decrease BCL2 expression, increase mitochondrial membrane permeability, and induce a caspase-dependent apoptotic cell death in resistant cells. Each of these effects is reversed by a caspase 8 (CASP8)-specific inhibitor that blocks enzyme-substrate binding. Thus, increased activation of NF-kappaB can alter sensitivity to tamoxifen by modulating CASP8 activity, with consequent effects on BCL2 expression, mitochondrial function, and apoptosis. These data provide significant new insights into how molecular signaling affects antiestrogen responsiveness and strongly suggest that a combination of parthenolide and tamoxifen may offer a novel therapeutic approach to the management of some ER-positive breast cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Apoptosis / drug effects
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Autophagy
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Blotting, Western
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Caspase 8 / genetics
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Caspase 8 / metabolism*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Membrane Permeability / drug effects
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm*
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Estrogen Antagonists / pharmacology
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Immunoprecipitation
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Luciferases / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Mitochondria / metabolism*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Sequestosome-1 Protein
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Signal Transduction
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Tamoxifen / analogs & derivatives
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Tamoxifen / pharmacology
Substances
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Adaptor Proteins, Signal Transducing
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ESR1 protein, human
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Estrogen Antagonists
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Estrogen Receptor alpha
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NF-kappa B
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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RNA, Small Interfering
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SQSTM1 protein, human
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Sequestosome-1 Protein
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Tamoxifen
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afimoxifene
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Luciferases
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Caspase 8