Vitamin D and HA Signaling in TNBC

TNBC 中的维生素 D 和 HA 信号转导

• 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
• 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

 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。在每年诊断患有乳腺癌的> 200，000名妇女中，15-25%被诊断患有缺乏雌激素和孕激素受体并且不表现出Her 2扩增的“三阴性”乳腺癌（TNBC）。这些肿瘤通常具有基底样基因表达特征，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1，25 D显著抑制透明质酸合酶-2（HAS 2）的表达和活性，HAS 2是一种在TNBC中优先过表达的基因。重要的是，肿瘤过表达HAS 2的TNBC女性的生存率显著降低，这表明靶向该基因可能对疾病进展产生影响。HAS 2编码一种产生透明质酸（HA）的酶，透明质酸是一种分泌的聚合物，可激活细胞表面受体CD 44，CD 44在功能上与获得“干细胞”或“肿瘤起始细胞”特性相关。有相当多的证据表明，TNBC的生存依赖于CD 44，但HAS 2和HA在介导这些作用中的作用尚未研究。该项目将测试TNBC依赖于HAS 2产生的HA来驱动CD 44介导的存活信号传导的假设。我们的初步数据强烈表明，维生素D抑制HAS 2活性和HA合成代表了中断TNBC细胞中CD 44信号传导的可行方法。拟议的研究将检查维生素D和其他三种天然产物（4-甲基伞形酮[4 MU]，磺基喹诺糖[SQ]和葡萄糖胺）对体外和体内TNBC模型中HA代谢和CD 44信号传导的独立和相互作用。如果我们的临床前研究表明，任何或所有这些药物对疾病进展的影响，我们建议，测量HA代谢的生化指标可能成为一个有用的屏幕，以确定乳腺癌患者谁是最有可能响应这些干预措施。因此，该项目的完成将提供关于在患有TNBC的妇女中使用这些药物的重要翻译信息。