Vitamin D and HA Signaling in TNBC

TNBC 中的维生素 D 和 HA 信号转导

• 批准号: 9453220
• 负责人: JoEllen Welsh
• 金额: $ 15.31万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 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/9453220
• 关键词: 4-methylumbelliferone; Amino Sugars; Anatomy; Apoptosis; Automobile Driving; Bioavailable; Biochemical; Breast Cancer Patient; CD44 gene; Cancer Patient; Cell Death; Cell Surface Receptors; Cell Survival; Cells; Characteristics; Chronic; Complex; Coumarins; Data; Data Set; Diagnosis; Diet; Dietary Component; Dietary Sugars; Dihydroxycholecalciferols; Disease; Disease Progression; Enzymes; Epithelial; Estrogen Receptors; Exhibits; Funding; Gene Expression Profile; Gene Targeting; Genes; Glucosamine; Goals; Grant; Growth; HAS2 gene; Hallmark Cell; Heterogeneity; Hexosamines; Hexoses; High Prevalence; Human; Hyaluronic Acid; In Vitro; Interruption; Intervention; Knockout Mice; Ligands; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Mesenchymal; Metabolism; Modeling; Molecular; Mus; Natural Products; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Nutrient; Ontology; Oral; Pathway interactions; Phenotype; Polymers; Polysaccharides; Population; Production; Progesterone Receptors; Property; Public Health; Recurrence; Regimen; Regulation; Relapse; Repression; Role; STAT3 gene; Secondary Prevention; Signal Transduction; Stem cells; Surface; Testing; Time; Translating; Treatment Protocols; Tumor Cell Line; Tumor Initiators; Tumorigenicity; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Woman; cancer cell; cancer genome; cancer stem cell; cancer survival; dietary approach; disorder subtype; in vitro Model; in vivo; malignant breast neoplasm; molecular subtypes; neoplastic cell; outcome forecast; overexpression; preclinical study; prevent; public health relevance; receptor; receptor expression; triple-negative invasive breast carcinoma; tumor; tumor progression; tumorigenesis; tumorigenic; virtual

 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，具有至少 4 种主要的分子定义亚型。每年有超过 200,000 名女性被诊断患有乳腺癌，其中 15-25% 被诊断为“三阴性”乳腺癌 (TNBC)，这种乳腺癌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，代表了该疾病最具侵袭性和致命性的亚型，治疗选择很少。在之前的资助期间，我们证明了维生素 D 的活性形式 1,25D 显着抑制透明质酸合酶 2 (HAS2) 的表达和活性，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 女性患者的生存率显着降低，这表明针对该基因可能会对疾病进展产生影响。 HAS2编码一种产生透明质酸（HA）的酶，透明质酸是一种分泌性聚合物，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，但尚未研究 HAS2 和 HA 在介导这些作用中的作用。该项目将测试以下假设：TNBC 依赖 HAS2 生成的 HA 来驱动 CD44 介导的生存信号传导。我们的初步数据强烈表明，维生素 D 抑制 HAS2 活性和 HA 合成是中断 TNBC 细胞中 CD44 信号传导的可行方法。拟议的研究将在体外和体内 TNBC 模型中检验维生素 D 和其他三种天然产物（4-methylumberellifone [4MU]、磺基喹诺糖 [SQ] 和葡萄糖胺）对 HA 代谢和 CD44 信号传导的独立和交互作用。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 代谢的生化指标可能会成为一个有用的筛选，以识别最有可能对这些干预措施产生反应的乳腺癌患者。因此，该项目的完成将提供有关在患有 TNBC 的女性中使用这些药物的重要转化信息。