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PKCθ promotes c-Rel–driven mammary tumorigenesis in mice and humans by repressing estrogen receptor α synthesis
Karine Belguise, Gail E. Sonenshein
Karine Belguise, Gail E. Sonenshein
Published December 3, 2007
Citation Information: J Clin Invest. 2007;117(12):4009-4021. https://doi.org/10.1172/JCI32424.
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Research Article Oncology

PKCθ promotes c-Rel–driven mammary tumorigenesis in mice and humans by repressing estrogen receptor α synthesis

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Abstract

The vast majority of primary human breast cancer tissues display aberrant nuclear NF-κB 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 α (ERα) signaling, and we identify an epigenetic mechanism in breast cancer mediated by activation of what we believe is a novel PKCθ-Akt pathway that leads to downregulation of ERα synthesis and derepression of c-Rel. ERα levels were lower in c-Rel–induced mammary tumors compared with normal mammary gland tissue. PKCθ induced c-Rel activity and target gene expression and promoted growth of c-Rel- and c-RelxCK2α–driven mouse mammary tumor–derived cell lines. RNA expression levels of PKCθ and c-Rel target genes were inversely correlated with ERα levels in human breast cancer specimens. PKCθ activated Akt, thereby inactivating forkhead box O protein 3a (FOXO3a) and leading to decreased synthesis of its target genes, ERα and p27Kip1. Thus we have shown that activation of PKCθ inhibits the FOXO3a/ERα/p27Kip1 axis that normally maintains an epithelial cell phenotype and induces c-Rel target genes, thereby promoting proliferation, survival, and more invasive breast cancer.

Authors

Karine Belguise, Gail E. Sonenshein

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Figure 4

PKCθ regulates c-Rel transcriptional activity and target gene expression.

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PKCθ regulates c-Rel transcriptional activity and target gene expression...
(A) WCEs (500 μg) from rel-3875 cells transfected with 6 μg PKCθ-K/R or EV were subjected to ONP assay as described in Figure 1D. (B) Left: rel-3875 cells were transfected with 0.025 μg pG5E1B-Luc, β-gal, or 0.01 μg Gal4 or Gal4–c-Rel, along with 0.4 or 0.8 μg PKCθ-K/R or EV, and processed as described in Figure 2D. Right panel, rel-3875 cells were transfected with 0.1 μg NF-κB–Luc, β-gal, and 0.2 μg PKCθ-K/R or EV. Values represent the mean (± SD) of normalized luciferase activities. (C) rel-3983 cells were transfected with 0.1 μg NF-κB–Luc, β-gal, and 0.2, 0.3, or 0.4 μg PKCθ-K/R or EV and processed as above. (D) rel-3875 cells were transfected with 0.05 μg pG5E1B-Luc, β-gal, 0.1 μg Gal4 or Gal4–c-Rel, and 0.2 μg PKCθ-A/E or EV (left panel) or with 0.1 μg NF-κB–Luc, β-gal, and 0.2 μg PKCθ-A/E or EV (right panel) and processed as above. (E) WCEs (1,000 μg) from MCF7 cells transfected with 6 μg PKCθ-A/E or EV were subjected to ONP assay. Input: 15 μg WCEs. (F) WCEs from MCF7 cells transfected with 1 μg PKCθ-A/E or EV plus 2 μg SR-IκBα or EV were subjected to immunoblotting. (G) rel-3875 cells were transfected with 0.1 μg cyclin D1 promoter driven–66-CD1-Luc and SV-40 β-gal in the presence of 0.2 μg PKCθ-A/E or EV (left panel) or 0.4 μg PKCθ-K/R or EV with either 0.2 μg c-Rel plus 0.2 μg p52 or EV (right panel). (H) WCEs from the indicated stable transfectants were subjected to immunoblotting.

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