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（由申请人提供）：三阴性乳腺癌[ER（-）/PR（-）/HER2wt（TNBC）]是高度侵袭性乳腺癌，经常发生在BRCA1突变携带者和非洲裔（AA）年轻女性中。患有 TNBC 的德系女性有 60% 的种系 BRCA1 突变发生率，而患有 TNBC 的白人女性和 AA 女性中，只有不到 40% 和 20% 携带种系 BRCA1 突变。我们发现了一种新的肿瘤抑制基因，即含有 WW 结构域的氧化还原酶 (WWOX)，并观察到 ​​WWOX 的缺失会激活糖酵解和葡萄糖摄取。在本提案中，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，并且葡萄糖摄取增加。 WWOX 缺乏与糖酵解增强和线粒体呼吸减弱有关，这与“瓦尔堡效应”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。在试点研究中，我们测试了人类乳腺组织中 WWOX 表达的缺失和 FLIM 代谢成像。我们观察到 WWOX 表达在 88% 的 TNBC 以及我们测试的所有 AA 女性中丢失。在这些初步研究中，我们观察到 WWOX 表达的丧失与高危非癌组织和 TNBC 中的高糖酵解代谢特征相关。总的来说，这些研究强调了肿瘤抑制因子 WWOX 在癌症发生过程中激活糖酵解和细胞代谢中的潜在作用。 我们的目标是从实验室到临床进行测试 假设临床前模型中肿瘤抑制因子 WWOX 1) 的缺失通过转录激活 HIF1a 机械地激活转移性 TNBC 中的糖酵解，而通过荧光寿命成像 (FLIM) 测量，原发性和转移性 TNBC 中的 2) 会激活代谢。目标 1 将测试 TNBC 中 WWOX 的丢失是否会通过 HIF1a 的转录激活来激活糖酵解。目标 2 将研究 WWOX 表达的缺失是否预示着 TNBC 进展和转移过程中代谢/糖酵解的增加。

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