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Vitamin D and HA Signaling in TNBC

TNBC 中的维生素 D 和 HA 信号传导

基本信息

批准号：
9041555
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/9041555
关键词：
4-methylumbelliferone Amino Sugars Anatomy Apoptosis Automobile Driving Bioavailable Biochemical 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 Dihydroxycholecalciferols Disease Disease Progression Enzymes Epithelial Estrogen Receptors Exhibits Funding Gene Expression Profile Gene Targeting Genes Glucosamine Goals Grant Growth HAS2 gene 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 Natural Products 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 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

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.