Triple-negative breast cancers [ER (-)/PR (-)/HER2wt (TNBC)] are highly aggressive breast cancers that frequently occur in BRCA1 mutation carriers and young women of African origin (AA). While Ashkenazi women with TNBC have a 60% incidence of germline BRCA1 mutation, less than 40% of Caucasian and only 20% of AA women with TNBC carry a germline BRCA1 mutation. We discovered a novel tumor suppressor gene, WW domain-containing oxidoreductase (WWOX) and observe 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. In preliminary data, we observe Wwox-deficient cells exhibit increased HIF1a and activity and display increased glucose uptake. WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, consistent with the 'Warburg effect'. Based on our preliminary data, we hypothesize that WWOX controls glycolytic genes' expression through regulation of HIF1a. In pilot studies, we tested for loss of WWOX expression and FLIM metabolic imaging in human breast tissue. We observe that WWOX expression is lost in 88% of TNBC, and in all AA women we tested. In these preliminary studies we observed that loss of WWOX expression correlated high glycolytic metabolic signatures in both non-cancerous tissue from high-risk and in TNBC. Taken together these studies highlight a potential role for the tumor suppressor WWOX in activating glycolysis and cellular metabolism during cancer initiation. Here we aim to test from the bench to the clinic the hypothesis that loss of the tumor suppressor WWOX 1) in preclinical models mechanistically activates of glycolysis in metastatic TNBC via transcriptional activation HIF1a and 2) in primary and metastatic TNBC activates metabolism as measured by Fluorescence Lifetime Imaging (FLIM).
Aim 1 will test whether loss of WWOX in TNBC activate glycolysis by transcriptional activation of HIF1a.
Aim 2 will investigate whether loss of WWOX expression predicts increased metabolism/glycolysis during progression and metastasis of TNBC.
Breast Magnetic Resonance Imaging (MRI) has revolutionized high-risk breast cancer screening. However, while breast MRI is extremely sensitive, MRI has poor specificity. As a result, women are required to undergo frequent breast biopsy and expensive repeat MRI imaging. The vast majority of these MRI-generated biopsies do not contain cancer but still require extensive follow-up.
|Dietze, Eric C; Sistrunk, Christopher; Miranda-Carboni, Gustavo et al. (2015) Triple-negative breast cancer in African-American women: disparities versus biology. Nat Rev Cancer 15:248-54|