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Despite the perception of many oncologists that tamoxifen is an inferior drug, and should be substituted by an aromatase inhibitor in post-menopausal women, the current evidence strongly supports the view that AIs should be used 2-3 years after tamoxifen to achieve the maximal overall survival (OS) advantage.

Nuclear factor-kappaB pathway (NF-kappaB) is activated in many breast cancers. NF-small kappaB has interactions with other pathways such as the nerve growth factor (NGF) pathway, which is involved in the survival and proliferation of breast cancer cells. NGF treatment of breast cancer cells activates NF-kappaB resulting in the inhibition of ceramide-induced apoptosis. NGF effects on apoptosis and cell proliferation are mediated through p75NTR and p140TrkA receptors, respectively. In this study we investigate the NGF/NF-kappaB pathway as a therapeutic target in breast cancer.We demonstrate that p75NTR inhibitor Pep5, p140TrkA inhibitor K-252a, and NF-kappaB inhibitor BAY11-7085 have pro-apoptotic and anti-proliferation activities in breast cancer cells. We also show a synergy in combining the NGF receptor inhibitors with the conventional breast cancer treatments tamoxifen and taxol.These data suggest that NGF/NF-kappaB pathway is a potential therapeutic target in breast cancer.

The DNA methyltransferase Dnmt1 is responsible for cytosine methylation in mammals and has a role in gene silencing. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MeCP2, which in turn recruits a histone deacetylase activity. Here we show that Dnmt1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, we find that one of the known histone deacetylases, HDAC1, has the ability to bind Dnmt1 and can purify methyltransferase activity from nuclear extracts. We have identified a transcriptional repression domain in Dnmt1 that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL-1). Our data show a more direct connection between DNA methylation and histone deacetylation than was previously considered. We suggest that the process of DNA methylation, mediated by Dnmt1, may depend on or generate an altered chromatin state via histone deacetylase activity.

Background We have previously demonstrated that BEX2 is differentially expressed in breast tumors and has a significant role in promoting cell survival and growth in breast cancer cells. BEX2 expression protects breast cancer cells against mitochondrial apoptosis and G1 cell cycle arrest. In this study we investigated the transcriptional regulation of BEX2 and feedback mechanisms mediating the cellular function of this gene in breast cancer. Results We found a marked induction of BEX2 promoter by c-Jun and p65/RelA using luciferase reporter assays in MCF-7 cells. Furthermore, we confirmed the binding of c-Jun and p65/RelA to the BEX2 promoter using a chromatin immunoprecipitation assay. Importantly, transfections of c-Jun or p65/RelA in MCF-7 cells markedly increased the expression of BEX2 protein. Overall, these results demonstrate that BEX2 is a target gene for c-Jun and p65/RelA in breast cancer. These findings were further supported by the presence of a strong correlation between BEX2 and c-Jun expression levels in primary breast tumors. Next we demonstrated that BEX2 has a feedback mechanism with c-Jun and p65/RelA in breast cancer. In this process BEX2 expression is required for the normal phosphorylation of p65 and IκBα, and the activation of p65. Moreover, it is necessary for the phosphorylation of c-Jun and JNK kinase activity in breast cancer cells. Furthermore, using c-Jun stable lines we showed that BEX2 expression is required for c-Jun mediated induction of cyclin D1 and cell proliferation. Importantly, BEX2 down-regulation resulted in a significant increase in PP2A activity in c-Jun stable lines providing a possible underlying mechanism for the regulatory effects of BEX2 on c-Jun and JNK. Conclusions This study shows that BEX2 has a functional interplay with c-Jun and p65/RelA in breast cancer. In this process BEX2 is a target gene for c-Jun and p65/RelA and in turn regulates the phosphorylation/activity of these proteins. These suggest that BEX2 is involved in a novel feedback mechanism with significant implications for the biology of breast cancer.