Combined breast MRI/biomarker strategies to identify aggressive biology

结合乳腺 MRI/生物标志物策略来识别侵袭性生物学

• 批准号: 9982221
• 负责人: STEVEN K CLINTON
• 金额: $ 64.99万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982221
• 关键词: African; African American; BRCA1 Mutation; Benign; Biochemical; Biological; Biological Markers; Biology; Biopsy; Biopsy Specimen; Breast Cancer Detection; Breast Magnetic Resonance Imaging; Breast biopsy; Caucasians; Cells; Contralateral Breast; Data; Development; Estrogen receptor positive; Exhibits; Family; Gene Expression; Glycolysis; Goals; High Risk Woman; Human; Image; Incidence; Lesion; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Mammaplasty; Mammary Gland Parenchyma; Mammary gland; Measures; Metabolic; Metabolism; Mitochondria; Molecular; Morphology; Mutation; Neoplasm Metastasis; Ohio; Oncogenic; Oxidoreductase; Pilot Projects; Play; Pre-Clinical Model; Regulation; Respiration; Risk; Role; Signal Transduction; Site; Specificity; TP53 gene; Testing; Tissues; Transcriptional Activation; Transgenic Mice; Tumor Suppressor Genes; Tumor Suppressor Proteins; Untranslated Regions; WNT Signaling Pathway; Warburg Effect; Wnt proteins; Woman; base; bench to bedside; breast lesion; cancer initiation; cohort; fluorescence lifetime imaging; follow-up; glucose uptake; high risk; improved; magnetic resonance imaging biomarker; malignant breast neoplasm; metabolic imaging; mutant; mutation carrier; novel; outcome forecast; overexpression; programs; prospective; public health relevance; screening; triple-negative invasive breast carcinoma; tumor; young woman

 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.

 描述(申请人提供)：三阴性乳腺癌[ER(-)/PR(-)/HER2wt(TNBC)]是一种高度侵袭性的乳腺癌，经常发生在BRCA1突变携带者和非洲裔年轻女性(AA)中。虽然患有TNBC的德系妇女有60%的BRCA1胚系突变，但只有不到40%的高加索人和只有20%的再生障碍性贫血妇女携带着种系BRCA1突变。我们发现了一个新的肿瘤抑制基因，WW结构域的氧化还原酶(WWOX)，并观察到WWOX的缺失激活了糖酵解和葡萄糖摄取。在这项建议中，我们旨在研究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HIF1a和活性增加，并表现出葡萄糖摄取增加。WWOX缺乏症与糖酵解增强和线粒体呼吸减弱有关，这与“Warburg效应”一致。根据我们的初步数据，我们假设WWOX通过调节HIF1a来控制糖酵解基因的表达。在先导性研究中，我们测试了WWOX在人类乳腺组织中的表达缺失和代谢成像。我们观察到，在88%的TNBC中，以及我们测试的所有AA女性中，WWOX的表达缺失。在这些初步研究中，我们观察到WWOX表达的缺失与高危非癌组织和TNBC中的高糖酵解代谢特征有关。综上所述，这些研究强调了肿瘤抑制基因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替补席到诊所进行测试 假设在临床前模型中肿瘤抑制基因WWOX的缺失通过转录激活HIF1a机械地激活转移性TNBC中的糖酵解，以及2)通过荧光寿命成像(FLIM)检测原发和转移性TNBC中的代谢激活。目的1检测TNBC中WWOX的缺失是否通过转录激活HIF1a来激活糖酵解。目的2研究WWOX表达缺失是否预示着TNBC在进展和转移过程中代谢/糖酵解增加。

项目成果

Racial Disparity in Quadruple Negative Breast Cancer: Aggressive Biology and Potential Therapeutic Targeting and Prevention.

• DOI: 10.3390/cancers14184484
• 发表时间: 2022-09-16
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Jinna, Nikita;Jovanovic-Talisman, Tijana;LaBarge, Mark;Natarajan, Rama;Kittles, Rick;Sistrunk, Christopher;Rida, Padmashree;Seewaldt, Victoria L.
• 通讯作者: Seewaldt, Victoria L.

Mammographic Density Laws and Inclusion-Time for Change.

• DOI: 10.1001/jamaoncol.2021.6196
• 发表时间: 2022-01-01
• 期刊: JAMA oncology
• 影响因子: 28.4
• 作者: Tossas KY;Winn RA;Seewaldt VL
• 通讯作者: Seewaldt VL