The receptor tyrosine kinase ErbB2 (HER-2/neu) is overexpressed in up to 30% of breast cancers and is associated with poor prognosis and an increased likelihood of metastasis especially in node-positive tumors. In this proteomic study, to identify the proteins that are associated with the aggressive phenotype of HER-2/neu-positive breast cancer, tumor cells from both HER-2/neu-positive and -negative tumors were procured by laser capture microdissection. Differentially expressed proteins in the two subsets of tumors were identified by two-dimensional electrophoresis and MALDI-TOF/TOF MS/MS. We found differential expression of several key cell cycle modulators, which were linked with increased proliferation of the HER-2/neu-overexpressing cells. Nine proteins involved in glycolysis (triose-phosphate isomerase (TPI), phosphoglycerate kinase 1 (PGK1), and enolase 1 (ENO1)), lipid synthesis (fatty acid synthase ( Traditional cancer chemotherapy agents designed to block cell division are toxic to healthy cells as well as to cancer cells. Targeting specific metabolic pathways to stop cancer growth is potentially less toxic to normal cells and can improve tolerability considerably. Thus, anticancer drug discovery has shifted from the traditional empiric random screening approach to a more rational and mechanistic, target-based approach whereby specific abnormalities in cell functioning are modulated in a classical drug (ligand)-receptor fashion. The HER/ErbB family of transmembrane receptors is one of the most exciting targets currently under evaluation.This ErbB family of receptor tyrosine kinases includes four closely related members: HER-1/ErbB1 (also known as the epidermal growth factor receptor), HER-2/ErbB2 (also known as HER-2/neu), 1 HER-3/ErbB3, and HER-4/ErbB4. These receptors initiate signals by forming ligand-induced combinations of homo-and heterodimers (1) and play a critical role in the pathogenesis of breast cancer. HER-2/neu, one of the most well characterized breast cancer oncogenes, is amplified in about 20 -30% of all human breast cancers (2, 3) and is also overexpressed in a variety of other human tumors, including ovarian, lung, gastric, and oral cancers. It appears

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BackgroundIncreasing evidence indicates that the interaction between the CXC chemokine receptor-4 (CXCR4) and its ligand CXCL12 is critical in the process of metastasis that accounts for more than 90% of cancer-related deaths. Thus, novel agents that can downregulate the CXCR4/CXCL12 axis have therapeutic potential in inhibiting cancer metastasis.MethodsIn this report, we investigated the potential of an agent, plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), for its ability to modulate CXCR4 expression and function in various tumor cells using Western blot analysis, DNA binding assay, transient transfection, real time PCR analysis, chromatin immunoprecipitation, and cellular migration and invasion assays.ResultsWe found that plumbagin downregulated the expression of CXCR4 in breast cancer cells irrespective of their HER2 status. The decrease in CXCR4 expression induced by plumbagin was not cell type-specific as the inhibition also occurred in gastric, lung, renal, oral, and hepatocellular tumor cell lines. Neither proteasome inhibition nor lysosomal stabilization had any effect on plumbagin-induced decrease in CXCR4 expression. Detailed study of the underlying molecular mechanism(s) revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, inhibition of NF-κB activation, and suppression of chromatin immunoprecipitation activity. In addition, using a virtual, predictive, functional proteomics-based tumor pathway platform, we tested the hypothesis that NF-κB inhibition by plumbagin causes the decrease in CXCR4 and other metastatic genes. Suppression of CXCR4 expression by plumbagin was found to correlate with the inhibition of CXCL12-induced migration and invasion of both breast and gastric cancer cells.ConclusionsOverall, our results indicate, for the first time, that plumbagin is a novel blocker of CXCR4 expression and thus has the potential to suppress metastasis of cancer.

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