Unknown,Transcriptomics,Genomics,Proteomics

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Investigate the anti-tumor mechanisms of But4ManNAc and butyrate in two breast cancer cell lines

ABSTRACT: But4ManNAc - an analog of ManNAc, the committed precursor of sialic acid - decreases metastatic potential, inhibits growth, and triggers apoptosis in many cancer cells. The anti-tumor effects of But4ManNAc may result from a synergistic interaction between butyrate-induced changes in gene expression and ManNAc-induced altered sialylation. This experiment provides insight into synergistic interactions by identifying changes in gene expression specific to But4ManNAc and not shared with butyrate. Specifically, microarrays will compare gene expression of metastatic breast cancer cells (MDA-MB-231) treated with But4ManNAc to that of cells treated with sodium butyrate at concentrations which inhibit invasiveness but do not trigger apoptosis. Differences in gene expression demonstrate a synergistic interaction between butyrate and sialylation as well as suggest mechanisms to account for this synergy. RNA preparations of treated and control metastatic breast cancer MDA-MB-231 cells were sent to Microarray Core (E). Five conditions where sent: cells treated with 50uM But4ManNAc, 125uM But4ManNAc, 50uM But5Man, 125uM But5Man, and Ethanol (control). Three replicate samples from each condition were used in the study. The RNA was amplified, labeled, and hybridized to the GLYCOv3 microarrays. Data was analyzed to identify differences in gene expression that demonstrate a synergistic interaction between butyrate and sialylation, as well as suggest mechanisms to account for this synergy.

ORGANISM(S): Homo sapiens

SUBMITTER: Steven Head

PROVIDER: E-GEOD-29922 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Statins and bisphosponates (BPs) are two distinct classes of isoprenoid pathway inhibitors targeting HMG-CoA reductase (upstream enzyme) and Farnesyl-pyrophospate synthase (downstream enzyme) respectively. Here we conducted a comparative study of two representatives of these classes, fluvastatin (Fluva) and Zoledronate (Zol), to assess the differences in their in vivo metastatic potentials and pharmacogenomic profiles. Both drugs, being administered after emergence of detectable metastases, appeared to be potent metastasis inhibitors in MDA-MB-231 breast cancer metastasis model. We observed a reduced number of metastatic sites under Fluva, but not Zol treatment. Combinatorial in vivo treatment by Fluva and Zol showed no synergy for these drugs, as reported earlier on the basis of in vitro studies (Budman DR, Oncology 2006), staying in line with similarity of their transcriptomic profiles. Comparison of Zol and Fluva transcriptomic profiles revealed similar patterns of affected genes (describe involved genes functions) through different kinetics (when treated with IC50 determined for 72h treatment, the majority of changes were observed after 24h incubation with Fluva , and only after 48h incubation with Zol at 72h-IC50 or after 24h treatment with its 3 times higher dose). We demonstrated here that targeting different enzymes of the same pathway neither necessarily leads to distinct changes in gene profiles, nor to synergy for in vivo anti-metastatic potential. Subconfluent MDA-MB-321 cells were treated with 2 ÂµM Fluvastatine or 30 ÂµM Zoledronate (concentrations corresponding to IC50 at 72h treatment) for 12h and 24h , or treated with Zoledronate for longer time (48h at 30 ÂµM) or with higher concentration (24h at 100 ÂµM of Zoledronate ). Mock-treated (control) cells were obtained in parallel for each time point. Four independent replicates were used for each condition. Total of 40 samples were analyzed (10 conditions with 4 replicates for each). To determine differentially expressed genes, differences between treated cells versus corresponding mock-treated control were calculated using R-Bioconductor statistical environment. Pairing was made to remove source of variation due to the day of measurement in the comparison between the two conditions.

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Investigate the anti-tumor mechanisms of But4ManNAc and butyrate in two breast cancer cell lines

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