Abstract
The vast majority of primary human breast cancer tissues display aberrant nuclear NF-kappaB c-Rel expression. A causal role for c-Rel in mammary tumorigenesis has been demonstrated using a c-Rel transgenic mouse model; however, tumors developed with a long latency, suggesting a second event is needed to trigger tumorigenesis. Here we show that c-Rel activity in the mammary gland is repressed by estrogen receptor alpha (ERalpha) signaling, and we identify an epigenetic mechanism in breast cancer mediated by activation of what we believe is a novel PKCtheta-Akt pathway that leads to downregulation of ERalpha synthesis and derepression of c-Rel. ERalpha levels were lower in c-Rel-induced mammary tumors compared with normal mammary gland tissue. PKCtheta induced c-Rel activity and target gene expression and promoted growth of c-Rel- and c-RelxCK2alpha-driven mouse mammary tumor-derived cell lines. RNA expression levels of PKCtheta and c-Rel target genes were inversely correlated with ERalpha levels in human breast cancer specimens. PKCtheta activated Akt, thereby inactivating forkhead box O protein 3a (FOXO3a) and leading to decreased synthesis of its target genes, ERalpha and p27(Kip1). Thus we have shown that activation of PKCtheta inhibits the FOXO3a/ERalpha/p27(Kip1) axis that normally maintains an epithelial cell phenotype and induces c-Rel target genes, thereby promoting proliferation, survival, and more invasive breast cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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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 Line, Tumor
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Cell Proliferation
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Cell Survival
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Estrogen Receptor alpha / biosynthesis*
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Estrogen Receptor alpha / genetics
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Female
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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Mammary Glands, Animal / metabolism
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Mammary Glands, Animal / pathology
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Mammary Glands, Human / metabolism
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Mammary Glands, Human / pathology
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Transgenic
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Neoplasm Invasiveness
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Phenotype
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Protein Kinase C / genetics
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Protein Kinase C / metabolism*
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Protein Kinase C-theta
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-rel / genetics
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Proto-Oncogene Proteins c-rel / metabolism*
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Signal Transduction / genetics
Substances
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CDKN1B protein, human
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Cdkn1b protein, mouse
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Estrogen Receptor alpha
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Proto-Oncogene Proteins c-rel
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Cyclin-Dependent Kinase Inhibitor p27
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Proto-Oncogene Proteins c-akt
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PRKCQ protein, human
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Protein Kinase C
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Protein Kinase C-theta