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The Roles Of Selenium Compounds In Inhibiting Proliferation And Metastasis Of Breast Cancer
Background: The migration of metastatic breast cancer cells involves chemoattraction of CXCR4 positive cells down a gradient of SDF-1 concentration. Thus, SDF-1 secreting tissues such as lung and bone marrow, chemoattract breast cancer cells. The essential trace element selenium is a potent anticancer agent at supranutritional levels. The mechanism of action of Se is unclear, but it involves apoptosis and changes in gene expression. This implies substantial changes in metabolism, which have yet to be examined systematically. Objectives: To investigate the impact of Se compounds on the metabolome of metastasizing breast cancer cells and the linkage to SDF-1 dependent cell mobility and gene expression in CXCR4 positive cells. This combined approach will produce a fuller understanding of the molecular physiology of breast cancer cell progression and Se-chemoprevention. Specific Aims: 1) To determine the efficacy of Se compounds on inhibition of cell growth and chemotaxis of murine and human breast cancer cell lines; 2) To determine the influence of Se compounds on global metabolism by NMR and GC/MS and gene expression by DNA micro arrays in breast cancer cells; 3) To integrate the metabolic and cell data with specific enzyme activities and gene expression. Study Design: The dose response of cell mobility and proliferation to three Se compounds, selenite, selneomethionine and methylseleninic acid, will be determined for two murine and human cancer cell lines differing in their estrogen responsiveness and metastatic potential. The optimum dose for the Se compounds on the different cell types will be used to measure the changes in intra- and extracellular metabolites and their metabolic pathways using C-13 labeled glucose with NMR and MS analysis. The metabolic data will be used to guide the design of quantitative analysis of gene expression by RT-PCR and gene arrays, and immunochemical analysis of proteins. Thus, changes at the gene or protein level can be related to the observed metabolic changes as a function of cell type and response to Se compounds. Benefits: Relating the metabolic profile and gene expression signatures of metastasizing breast cancer cells will give a molecular understanding of metastasis, and aid biomarker discovery. The metabolic and gene profiling of different Se compounds gives a molecular basis to the efficacy and mechanisms of their toxicity to breast cancer cells, which underlies the basis of dietary prophylactic use of Se.
Breast cancer is the major cause of cancer-related deaths in women worldwide. According to NCI statistics, breast cancer has a high incidence rate (1 in 8 women), and a high mortality rate (lifetime risk of death is around 1 in 28). For these reasons, there has been intense research effort into understanding the origins of breast cancer and therapeutic strategies. The incidence rate is partly a consequence of genetic predisposition (less than 10% of all breast cancers), but also from environmental effects such as changes in the hormone estrogen. Breast cancer has a high mortality rate largely because of its tendency to spread (metastasize) to other tissues such as lung and bone. Metastasis involves cancer cells breaking loose from a primary site and traveling through the blood or lymph system, to another tissue where they may lodge and proliferate. Research has shown that such metastasing cancer cells are attracted to certain tissues. These cells have a receptor called CXCR4 on their surface that is normally involved in cell mobility, such as in inflammation. The receptor is activated by a small protein, SDF-1, which is a chemokine. Cells that secrete SDF-1, such as bone marrow and lung, act as transmitters in which SDF-1 is the signal. The CXCR4-positive cells are the receivers. Because they are mobile, they are attracted by, and migrate toward the source. Current drug treatments for breast cancer have a number of drawbacks, including lack of specificity, efficacy, side effects, cancer promotion in other tissue and limited applicability in metastasis. Selenium has been shown to be a useful anticancer dietary supplement. Although essential in low doses, at higher doses it is selectively toxic to cancer cells in humans. How selenium compounds act remains largely unknown. Our goal is to determine the inhibitory effects of different selenium compounds on the growth and metastasis of different breast cancer cells, and how this is mediated through the CXCR4/SDF-1 interaction. We will also use a combination of technologies including nuclear magnetic resonance (NMR), mass spectrometry (MS) and gene arrays to measure globally the metabolic and gene expression signatures associated with metastatic and non-metastatic breast cancer cells, in response to selenium. This information will contribute to a mechanistic understanding of breast cancer progression, discovery of metastatic markers for diagnostics and design of selenium supplementation as a means for breast cancer prevention.