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Delineating racially distinct metabolic pathways in triple negative breast cancer

Arun Sreekumar

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National Institutes of Health (NIH)
The long-term objective of our research plan is to reduce the disproportionate effects of Triple Negative Breast Cancer on African American women. A guiding principle of our methodology is metabolic differences exist between triple negative breast cancers of African American and European American origin and that these differences can explain, in part, breast cancer health disparity. In this application, we propose t use the technique of metabolomic measurements to uncover these underlying differences. Metabolomics describes the science of quantifying the levels of metabolites (e.g., small molecules) that are the byproducts of cellular metabolism. In other words, in this kind of analysiswe are measuring the biochemical entities (or metabolites) that are produced by the functional machinery of the cell. With knowledge of the identity of specific metabolites we can infer the biological processes that produced them, thus gaining insight into a cell's metabolism. We have recently published the first study describing metabolic alterations associated with triple negative breast cancer in African-American women. We identified alterations in two key biochemical pathways namely those involved in metabolism of 2-hydroxyglutarate and arachidonic acid, both of which were elevated in a subset of African-American triple negative breast cancers having a poor clinical outcome. In this application we propose to follow up on these findings by 1) validating elevated levels of fatty acids (including arachidonic acid) and phospholipids in independent set of triple negative breast cancer tissues from African-American women 2) characterize the mechanisms causing accumulation of 2-hydroxyglutarate and arachidonic acid in African-American women and 3) develop a first-generation panel of prognostic metabolic markers for African-American women using metabolites in the 2-hydroxyglutarate and fatty acid pathway. At the conclusion of this study, we will have developed a racially derived metabolomic model for triple negative breast cancer as well as identified candidate pathways for future drug targeting.

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