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

The vast majority of primary human breast cancer tissues display aberrant nuclear NF-kappa B 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 (ER alpha) signaling, and we identify an epigenetic mechanism in breast cancer mediated by activation of what we believe is a novel PKC theta-Akt pathway that leads to downregulation of ER alpha synthesis and derepression of c-Rel. ER alpha levels were lower in c-Rel-induced mammary tumors compared with normal mammary gland tissue. PKC theta induced c-Rel activity and target gene expression and promoted growth of c-Rel- and c-ReNCK2 alpha-driven mouse mammary tumor-derived cell lines. RNA expression levels of PKC theta and c-Rel target genes were inversely correlated with ERa levels in human breast cancer specimens. PKC theta activated Akt, thereby inactivating forkhead box O protein 3a (FOXO3a) and leading to decreased synthesis of its target genes, ERa and p27(KiP1). Thus we have shown that activation of PKC theta inhibits the FOXO3a/ER alpha/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.