Delineating racially distinct metabolic pathways in triple negative breast cancer

描述(由申请人提供)：我们研究计划的长期目标是减少三阴性乳腺癌对非裔美国女性的不成比例的影响。我们方法学的指导原则是，非裔美国人和欧洲裔美国人起源的三重阴性乳腺癌之间存在代谢差异，这些差异可以部分解释乳腺癌健康差异。在这个应用中，我们建议使用代谢测量技术来揭示这些潜在的差异。代谢组学描述了对细胞代谢副产物代谢物(例如小分子)水平进行量化的科学。换句话说，在这种分析中， 我们正在测量由细胞功能机械产生的生化实体(或代谢物)。通过了解特定代谢物的特性，我们可以推断产生这些代谢物的生物过程，从而深入了解细胞的新陈代谢。我们最近发表了第一项研究，描述了与三重阴性相关的代谢变化 非裔美国女性中的乳腺癌。我们确定了两个关键的生化途径的变化，即参与2-羟基戊二酸和花生四烯酸代谢的那些，这两个途径在临床预后较差的非裔美国人三阴性乳腺癌中都升高。在这项应用中，我们建议通过以下方式对这些发现进行后续研究：1)验证非裔美国女性三重阴性乳腺癌组织中脂肪酸(包括花生四烯酸)和磷脂水平的升高；2)表征导致非裔美国女性2-羟基戊二酸和花生四烯酸积累的机制；3)利用2-羟基戊二酸和脂肪酸途径中的代谢物，为非裔美国女性开发第一代预后代谢标志物小组。在这项研究的结论中，我们将开发一个种族衍生的三阴性乳腺癌的代谢组学模型，并确定未来药物靶向的候选途径。

DESCRIPTION (provided by applicant): 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 analysis we 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.