Folate, DNA Methylation and Breast Tumorigenesis

叶酸、DNA 甲基化和乳腺肿瘤发生

• 批准号: 7430490
• 负责人: JOSHUA WILLIAM MILLER
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430490
• 关键词: Aberrant DNA Methylation; Address; Affect; Appendix; Area; Attention; Binding; Binding Proteins; Biological Assay; Breast; Breast Carcinoma; California; Candidate Disease Gene; Carcinoma; Cells; Characteristics; Chemoprevention; Choline; Chronic; Class; DNA; DNA Methylation; Deoxycytidine; Diet; ERBB2 gene; Epigenetic Process; Estrogen receptor positive; Exhibits; Fatty acid glycerol esters; Fluorouracil; Folate; Folic Acid; Folic Acid Deficiency; Gene Expression; Gene Expression Microarray Analysis; Gene Targeting; Genes; Goals; Growth; Human; Human Mammary Carcinoma; Hypermethylation; Image; Incidence; Intake; Intraepithelial Neoplasia; Invasive; Lesion; Malignant - descriptor; Malignant Neoplasms; Malnutrition; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Methionine; Methotrexate; Methylation; Modeling; Molecular; Molecular Profiling; Monitor; Mouse Mammary Tumor Virus; Mus; Noninfiltrating Intraductal Carcinoma; Nutritional; Outcome; Patients; Pharmaceutical Preparations; Play; Polyomavirus; Population; Premalignant; Process; Promoter Regions; Proteins; Rate; Repression; Research; Research Personnel; Risk; Role; Signal Transduction Pathway; Study models; Testing; Thinking; Transcriptional Regulation; Transgenes; Transgenic Mice; Transplantation; Tumor Suppressor Genes; Tumor-Derived; Universities; Vitamin B Complex; bioactive food component; bisulfite; cancer cell; cancer prevention; chromatin immunoprecipitation; demethylation; dietary excess; feeding; folic acid metabolism; fortification; in vivo; inhibitor/antagonist; malignant breast neoplasm; mouse model; neoplastic; prevent; programs; promoter; research study; size; thymidylate; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Aberrant DNA methylation is a characteristic of cancer cells, including mammary tumors. Cancer cell DNA is typically hypomethylated, but exhibits areas of hypermethylation, particularly in the promoter regions of genes that protect cells from tumorigenic transformation (e.g. tumor suppressor genes). Such hypermethylation, mediated by methyl-CpG-binding proteins, inhibits gene expression, suggesting that demethylation of these genes may prove beneficial in controlling or reversing the tumorigenesis process. The B vitamin, folate, is required for the synthesis of S-adenosylmethionine, the methyl donor for DNA methylation. Alterations in folate status may affect DNA methylation during tumorigenesis. The overall goal of this proposal is to assess the influence of folate status and demethylation of DNA on the transformation of premalignant mammary lesions to malignancy. The hypotheses to be tested are: 1) premalignant mammary lesion growth and tumor incidence and size are decreased, and tumor latency is prolonged in folate-deficient mice and in mice treated with the DNA-demethylating agent, 5-aza-deoxycytidine, compared with folate-replete controls, 2) premalignant lesion growth and tumor incidence and size are increased, and tumor latency is reduced in mice fed excess folate compared with folate-replete controls, and 3) a subset of hypermethylated genes are demethylated and consequently become over-expressed in premalignant mammary lesions from both folate-deficient and 5-aza-deoxycytidine-treated mice compared with folate- replete and folate-excess mice. To test these hypotheses, premalignant, estrogen receptor positive mammary lesions, known as mammary intraepithelial neoplasia outgrowths (MIN-O's), with an established and consistent rate of malignant transformation, will be transplanted into the mammary fat pads of mice fed folate-replete, deficient, and excess diets, as well as in folate-replete mice exposed to 5-aza-deoxycytidine. MIN-O growth, tumor latency, incidence and size, pathological characterizations, gene expression profiles, gene-specific promoter methylation, arid gene targeting by methyl-CpG-binding proteins will be compared among the treatment groups. It is expected that these studies will demonstrate roles of folate and DNA methylation in mammary tumorigenesis, and will identify specific hypermethylated genes that contribute to the transition from premalignant mammary lesions to malignancy.

描述（由申请人提供）：异常DNA甲基化是癌细胞（包括乳腺肿瘤）的特征。癌细胞DNA通常是低甲基化的，但表现出高甲基化的区域，特别是在保护细胞免受致瘤性转化的基因（例如肿瘤抑制基因）的启动子区。这种由甲基CpG结合蛋白介导的高甲基化抑制基因表达，表明这些基因的去甲基化可能有助于控制或逆转肿瘤发生过程。B族维生素叶酸是合成S-腺苷甲硫氨酸所必需的，S-腺苷甲硫氨酸是DNA甲基化的甲基供体。叶酸状态的改变可能会影响肿瘤发生过程中的DNA甲基化。该建议的总体目标是评估叶酸状态和DNA去甲基化对乳腺癌前病变转化为恶性肿瘤的影响。待检验的假设为：1）与叶酸充足的对照相比，在叶酸缺乏的小鼠中和在用DNA-去甲基化剂5-氮杂-脱氧胞苷处理的小鼠中，癌前乳腺病变生长和肿瘤发生率和大小降低，并且肿瘤潜伏期延长，2）癌前病变生长和肿瘤发生率和大小增加，并且与叶酸充足的对照组相比，在喂食过量叶酸的小鼠中肿瘤潜伏期减少，和3）高甲基化基因的子集被去甲基化，因此在叶酸缺乏和5-氮杂-脱氧胞苷引起的癌前乳腺病变中过度表达。与叶酸充足和叶酸过量的小鼠相比。为了检验这些假设，将具有确定的和一致的恶性转化率的癌前雌激素受体阳性乳腺病变（称为乳腺上皮内瘤形成副产物（MIN-O's））移植到喂食叶酸充足、缺乏和过量饮食的小鼠以及暴露于5-氮杂脱氧胞苷的叶酸充足小鼠的乳腺脂肪垫中。将比较治疗组之间的MIN-O生长、肿瘤潜伏期、发病率和大小、病理学特征、基因表达谱、基因特异性启动子甲基化和甲基-CpG结合蛋白的基因靶向。预计这些研究将证明叶酸和DNA甲基化在乳腺肿瘤发生中的作用，并将确定特定的高甲基化基因，这些基因有助于从癌前乳腺病变转变为恶性肿瘤。

项目成果

Folate, DNA methylation, and mouse models of breast tumorigenesis.

• DOI: 10.1111/j.1753-4887.2008.00070.x
• 发表时间: 2008-08
• 期刊: Nutrition reviews
• 影响因子: 6.1
• 作者: Miller JW;Borowsky AD;Marple TC;McGoldrick ET;Dillard-Telm L;Young LJ;Green R
• 通讯作者: Green R