Vitamin D and HA Signaling in TNBC

TNBC 中的维生素 D 和 HA 信号转导

基本信息

批准号：
8874348
负责人：
JoEllen Welsh
金额：
$ 35.23万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874348
关键词：
1,25 (OH) vitamin D 4-methylumbelliferone Amino Sugars Anatomy Apoptosis Automobile Driving Bioavailable Biochemical Biological Factors Breast Cancer Cell Breast Cancer Model Breast Cancer Patient CD44 gene Cancer Patient Cell Death Cell Separation Cell Surface Receptors Cell Survival Cells Characteristics Chronic Complex Coumarins Data Data Set Diagnosis Diet Dietary Component Dietary Sugars Disease Disease Progression Enzymes Epithelial Estrogen Receptors Exhibits Funding Gene Expression Profile Gene Targeting Genes Glucosamine Goals Grant Growth Heterogeneity Hexosamines Hexoses High Prevalence Human Hyaluronic Acid In Vitro Intervention Knockout Mice Life Ligands Malignant Neoplasms Mammary Neoplasms Measures Mediating Mesenchymal Metabolism Modeling Molecular Mus Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Nutrient Ontology Pathway interactions Phenotype Polymers Polysaccharides Population Production Progesterone Receptors Property Public Health Recurrence Regimen Regulation Relapse Repression Role STAT3 gene Secondary Prevention Signal Transduction Staging Stem cells Surface Testing Time Translating Treatment Protocols Tumor Cell Line Vitamin D Vitamin D Deficiency Vitamin D3 Receptor Woman cancer genome cancer stem cell dietary approach disorder subtype hyaluronan synthase 1 in vivo malignant breast neoplasm neoplastic cell outcome forecast overexpression preclinical study prevent public health relevance receptor receptor expression triple-negative invasive breast carcinoma tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is a heterogeneous disease with at least 4 major molecularly defined sub-types. Of the >200,000 women diagnosed with breast cancer annually, between 15-25% are diagnosed with "triple negative" breast cancer (TNBC) which lack estrogen and progesterone receptors and do not exhibit amplification of Her2. These tumors usually have basal-like gene expression signatures and represent the most aggressive and lethal subtype of the disease with few treatment options. During the previous funding period we demonstrated that 1,25D, the active form of vitamin D, markedly suppresses the expression and activity of hyaluronan synthase-2 (HAS2), a gene that is preferentially overexpressed in TNBC. Importantly, women with TNBC whose tumors overexpress HAS2 have significantly reduced survival, suggesting that targeting this gene is likely to have an impact on disease progression. HAS2 encodes an enzyme that produces hyaluronic acid (HA) a secreted polymer that activates the cell surface receptor CD44 which has been functionally associated with the acquisition of "stem-cell" or "tumor initiating cell" properties. There is considerable evidence tht TNBCs are dependent on CD44 for survival, but the role of HAS2 and HA in mediating these effects have not been studied. This project will test the hypothesis that TNBCs are dependent on HAS2-generated HA to drive CD44 mediated survival signaling. Our preliminary data strongly suggests that vitamin D suppression of HAS2 activity and HA synthesis represents a feasible approach for interrupting CD44 signaling in TNBC cells. The proposed studies will examine the independent and interactive effects of vitamin D and three other natural products (4-methylumberellifone [4MU], sulfoquinovose [SQ] and glucosamine) on HA metabolism and CD44 signaling in TNBC models in vitro and in vivo. If our pre-clinical studies demonstrate that any or all of these agents impact on disease progression, we propose that measuring biochemical measures of HA metabolism could become a useful screen to identify breast cancer patients who are most likely to respond to these interventions. Completion of this project will thus provide important translational information regarding the use of these agents in women living with TNBC.

描述（由申请人提供）：乳腺癌是一种异质性疾病，至少有 4 种主要的分子定义亚型，每年诊断出患有乳腺癌的超过 200,000 名女性中，15-25% 被诊断为“三阴性”乳腺癌（ TNBC）缺乏雌激素和孕激素受体，并且不表现出 Her2 扩增，这些肿瘤通常具有类似基底细胞的基因表达特征，代表最具侵袭性和致命性的亚型。在之前的资助期间，我们证明了维生素 D 的活性形式 1,25D 可以显着抑制透明质酸合酶 2 (HAS2) 的表达和活性，而透明质酸合酶 2 (HAS2) 是一种在 TNBC 中优先过度表达的基因。重要的是，肿瘤过度表达 HAS2 的 TNBC 女性的生存率显着降低，这表明针对该基因可能会影响疾病进展，HAS2 编码一种产生透明质酸的酶。 (HA) 一种分泌性聚合物，可激活细胞表面受体 CD44，其功能与“干细胞”或“肿瘤起始细胞”特性的获得相关。有大量证据表明 TNBC 的生存依赖于 CD44，但HAS2 和 HA 在介导这些作用中的作用尚未得到研究，该项目将有力地检验 TNBC 依赖于 HAS2 生成的 HA 来驱动 CD44 介导的生存信号传导的假设。表明维生素 D 抑制 HAS2 活性和 HA 合成是中断 TNBC 细胞中 CD44 信号传导的一种可行方法。拟议的研究将检查维生素 D 和其他三种天然产物（4-methylumberellifone [4MU]、sulfoquinovose）的独立和交互作用。 [SQ] 和葡萄糖胺）对体外和体内 TNBC 模型中 HA 代谢和 CD44 信号传导的影响如果我们的临床前研究证明任何或所有这些药物都会影响疾病进展，我们建议，测量HA代谢的生化指标可以成为一个有用的筛选，以识别最有可能对这些干预措施做出反应的乳腺癌患者。因此，该项目的完成将为TNBC女性使用这些药物提供重要的转化信息。。