Despite vast improve ment in the overall survival rate of patients with nonin vasive breast cancer, advanced metastatic breast cancer remains a life threatening disease. One of the main chal lenges in mammary cancer research is now thenthereby to identify key proteins modulating tumor invasion, which can serve as early markers for invasive tumors as well as new drug targets. The serine threonine kinase protein kinase D1 in normal ductal epithelial cells of the breast maintains the epithelial phenotype and prevents epithelial to mes enchymal transition, an initial step required for cells to become motile and invasive. Because local in vasion is a necessary first step in metastatic dissemin ation to distant organs, the potential of cells to undergo EMT also defines the metastatic potential of the tumor.

In addition to its inhibitory effects on EMT, PKD1 negatively affects directed cell migration by blocking actin reorganization processes at the leading edge of mi grating cells. Furthermore, the expression Inhibitors,Modulators,Libraries and ac tivity of PKD1 regulate the invasiveness Inhibitors,Modulators,Libraries of breast cancer cell lines by inhibiting Inhibitors,Modulators,Libraries the expression of multiple matrix metalloproteinases. In breast cancer, PKD1 may be a key protein that inhibits the invasive pheno type, since a knockdown of PKD1 expression by reverse genetics has been shown to increase the invasiveness of the non or minimally motile MCF 7 cells. Moreover, highly invasive MDA MB 231 cells that do not express PKD1 were found to become noninvasive when active PKD1 was expressed.

Published transcriptional microarray data profiling over 350 advanced breast tumors tissues have shown a dra matic decrease of PRKD1 gene expression in most tumor cases. These data are in accordance with signifi cantly reduced PKD1 expression detected in human cases of invasive ductal carcinoma and metastatic IDC compared Inhibitors,Modulators,Libraries to samples of normal breast epithelium. However, no data are available on how PKD1 expression Inhibitors,Modulators,Libraries is negatively regulated during breast tumor progression. Aberrant epigenetic regulation of genes is one of the earliest and most frequent alteration in cancer cells and can lead to dramatic changes in cell phenotype and con tribute to breast carcinogenesis. Different types of genes are silenced by this manner, including tumor sup pressor genes, DNA repair genes or genes that suppress invasion and metastasis.

In contrast to genetic normally muta tions, epigenetic modifications such as DNA methylation are reversible and represent very promising therapeutic targets for breast cancer treatment. The goal of this study was to determine if epigenetic silencing of PRKD1 occurs in invasive cancer and whether this can be a driver of breast cancer cell metas tasis. By comparing normal and tumor patient tissue as well as normal, noninvasive, and highly invasive breast cancer cell lines, we show that PRKD1 gene promoter methylation directly correlates with the loss of PKD1 ex pression and the invasive potential of breast tumors or cells.