Abstract
FOXP3 is inactivated in breast cancer cells by a number of mechanisms, including somatic mutations, deletion, and epigenetic silencing. Because the mutation and deletion are usually heterozygous in the cancer samples, it is of interest to determine whether the gene can be induced for the purpose of cancer therapy. Here, we report that anisomycin, a potent activator of activating transcription factor (ATF) 2, and c-Jun-NH(2)-kinase, induces expression of FoxP3 in both normal and malignant mammary epithelial cells. The induction is mediated by ATF2 and c-Jun. Targeted mutation of ATF2 abrogates both constitutive and inducible expression of FoxP3 in normal epithelial cells. Both ATF2 and c-Jun interact with a novel enhancer in the intron 1 of the FoxP3 locus. Moreover, shRNA silencing of ATF2 and FoxP3 reveals an important role of ATF2-FoxP3 pathway in the anisomycin-induced apoptosis of breast cancer cells. A low dose of anisomycin was also remarkably effective in treating established mammary tumor in the mice. Our data showed that FoxP3 can be reactivated for cancer therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Activating Transcription Factor 2 / genetics
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Activating Transcription Factor 2 / metabolism*
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Animals
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Anisomycin / pharmacology
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Apoptosis / drug effects
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Binding Sites / genetics
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Blotting, Western
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Cell Line, Tumor
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Cells, Cultured
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Chromatin Immunoprecipitation
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Dose-Response Relationship, Drug
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Enhancer Elements, Genetic / genetics
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Enzyme Inhibitors / pharmacology
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Female
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gene Expression / drug effects
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Gene Expression / genetics
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Male
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred Strains
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Mice, Knockout
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Protein Synthesis Inhibitors / pharmacology
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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Activating Transcription Factor 2
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Atf2 protein, mouse
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Enzyme Inhibitors
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Protein Synthesis Inhibitors
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Anisomycin
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JNK Mitogen-Activated Protein Kinases