1. PKCtheta promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor alpha synthesis.
- Author
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Belguise K and Sonenshein GE
- Subjects
- Animals, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cyclin-Dependent Kinase Inhibitor p27 genetics, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Estrogen Receptor alpha genetics, Female, Forkhead Box Protein O3, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Isoenzymes genetics, Mammary Glands, Animal metabolism, Mammary Glands, Animal pathology, Mammary Glands, Human metabolism, Mammary Glands, Human pathology, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental pathology, Mice, Mice, Transgenic, Neoplasm Invasiveness, Phenotype, Protein Kinase C genetics, Protein Kinase C-theta, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-rel genetics, Signal Transduction genetics, Breast Neoplasms metabolism, Estrogen Receptor alpha biosynthesis, Isoenzymes metabolism, Mammary Neoplasms, Experimental metabolism, Protein Kinase C metabolism, Proto-Oncogene Proteins c-rel metabolism
- 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.
- Published
- 2007
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