Triple-negative breast cancers [ER(-)/PR(-)/HER2wt (TNBC)] are highly aggressive breast cancers that frequently occur in BRCA1 mutation carriers. While Ashkenazi women with TNBC have a 48% incidence of germline BRCA1 mutations, over 50% of Ashkenazi women lack a BRCA1 mutation. The team discovered a novel tumor suppressor gene, WW domaincontaining oxidoreductase (WWOX) whose loss promotes progression and metastasis of TNBC. The preliminary data provide evidence that loss of WWOX activates glycolysis and glucose uptake. In this proposal, we aim to investigate the role of WWOX signaling in activating metabolism in TNBC. Aim 1 will test whether loss of WWOX in TNBC activate glycolysis by transcriptional activation of HIF1α. Aim 2 will investigate whether loss of WWOX expression predicts increased metabolism/glycolysis in TNBC and noncancerous mammary epithelial cells from high-risk women. These studies are directly relevant to cancer because they investigate a signaling pathway that promotes metastasis and aggressive biology of TNBC. The long-term goal of this project is to identify new targets for early detection and treatment of TNBC.