Combined breast MRI/biomarker strategies to identify aggressive biology

 描述（由申请方提供）：三阴性乳腺癌[ER（-）/PR（-）/HER 2 wt（TNBC）]是高度侵袭性乳腺癌，常发生于BRCA 1突变携带者和非洲裔（AA）年轻女性。虽然患有TNBC的德系妇女有60%的生殖系BRCA 1突变发生率，但只有不到40%的高加索人和20%的AA女性携带生殖系BRCA 1突变。我们发现了一个新的肿瘤抑制基因，WW域含有氧化还原酶（WWOX），并观察到WWOX的损失激活糖酵解和葡萄糖摄取。在这个提议中，我们的目标是研究WWOX信号在激活TNBC代谢中的作用。 在初步数据中，我们观察到Wwox缺陷细胞表现出增加的HIF 1a和活性，并显示增加的葡萄糖摄取。WWOX缺乏与糖酵解增强和线粒体呼吸减少相关，与“瓦尔堡效应”一致。基于我们的初步数据，我们假设WWOX通过调节HIF 1a来控制糖酵解基因的表达。在初步研究中，我们测试了人类乳腺组织中WWOX表达的丧失和FLIM代谢成像。我们观察到，WWOX表达在88%的TNBC和我们测试的所有AA女性中丢失。在这些初步研究中，我们观察到WWOX表达的丧失与来自高风险和TNBC的非癌组织中的高糖酵解代谢特征相关。总之，这些研究突出了肿瘤抑制因子WWOX在癌症发生过程中激活糖酵解和细胞代谢的潜在作用。 在这里，我们的目标是从实验室到诊所进行测试 假设肿瘤抑制因子WWOX的丧失1）在临床前模型中通过转录激活HIF 1a机械地激活转移性TNBC中的糖酵解，和2）在原发性和转移性TNBC中激活代谢，如通过荧光寿命成像（FLIM）测量的。目的1将测试TNBC中WWOX的损失是否通过HIF 1a的转录激活来激活糖酵解。目的2将研究WWOX表达的丧失是否预测TNBC进展和转移期间代谢/糖酵解的增加。

 DESCRIPTION (provided by applicant): 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.