Determinants of Chemoprevention by SERMs

SERM 化学预防的决定因素

基本信息

批准号：
7320623
负责人：
MONICA MONTANO
金额：
$ 7.73万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7320623
关键词：
Accounting Address Animal Model Aromatase Binding Proteins Biological Models Breast Breast Carcinoma Carcinogens Cell Line Chemoprevention Chemopreventive Agent Complement Cultured Cells DNA DNA Damage Development Development, Other Dissection Enzymes Epithelial Cells Estrogen Antagonists Estrogen Metabolism Estrogen Receptor Modulators Estrogen Receptor beta Estrogen Receptors Estrogens Exposure to Genes Genetic Transcription Glutamate-Cysteine Ligase Glutathione S-Transferase Homologous Gene Human In Vitro Invasive Lesion Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Mitotic Modeling Molecular Target Mus NAD(P)H Dehydrogenase (Quinone)NAD(P)H dehydrogenase (quinone) 1, human NQO1 gene New Agents Nude Mice Pharmaceutical Preparations Positioning Attribute Premalignant Prevention Preventive Process Protein Overexpression Quinone Reductases Raloxifene Regulation Relative (related person)Research Response Elements Risk Risk Reduction Role Selective Estrogen Receptor Modulators Stress Tamoxifen Testing Thinking Time Transcriptional Regulation Transgenic Organisms Up-Regulation Validation Xenograft procedure Xenopus adduct base cancer prevention cell transformation gamma-glutamylcysteine genotoxicity in vivo insight malignant breast neoplasm mouse model novel prevent prophylactic protective effect receptor binding response tumor tumor growth tumor initiation tumorigenic

项目摘要

DESCRIPTION (provided by applicant): While it is widely accepted that the risk of developing breast cancer is directly related to one's lifetime exposure to estrogen, the precise role of estrogen in the initiation and progression of breast cancer has yet to be determined. It has been hypothesized that initiation may result from induction of further DNA damage by estrogen metabolites in concert with preexisting lesions, while upregulation of mitogenic genes through the estrogen receptor (ER) may facilitate progression. While there is strong evidence that estrogen metabolites are tumorigenic in in vitro and animal models, the idea that estrogen metabolites can act as genotoxic carcinogens has existed for quite some time but remains controversial. Our previous studies have shown that the antioxidative stress enzymes, such as Quinone Reductase (QR) and Glutathione S-transferase Pi, are upregulated in response to the antiestrogen tamoxifen in breast epithelial cell lines. Our further dissection of transcriptional regulation of antioxidative enzymes has shown that this regulation involves Estrogen Receptor beta (ER initial study of the functional role for ER against estrogen-induced DNA damage. By identifying factors that inhibit estrogen-induced DNA damage we are in a good position to verify the role of estrogen metabolites in DNA damage and breast tumor initiation, and cancer prevention by antioxidative stress enzymes. Based on our findings we hypothesize that ER enzymes protects against the genotoxic effects of estrogens and thus prevents estrogen-mediated breast tumor initiation. To test our hypothesis we propose to determine: (1) What are the determinants of mammary tumorigenesis chemoprevention by antiestrogens? (2) Can QR inhibit the development of estrogen- induced early mammary cancer? Our proposed studies should provide important insights into the basis for cancer preventive effects of Selective Estrogen Receptor Modulators (SERMs). We will also develop new research models to test mammary cancer chemopreventive potential of SERMs. These mechanistic studies are critical for developing molecular-targeted approaches for chemoprevention, and the development of other models for testing promising new agents.

描述（由申请人提供）：尽管人们广泛认为，乳腺癌的风险与一个人的终生暴露直接相关，但雌激素在乳腺癌的启动和进展中的确切作用尚未确定。据推测，起始可能是由于雌激素代谢产物与先前存在的病变一致的诱导DNA损伤而引起的，而通过雌激素受体（ER）对有丝分裂基因的上调可能会促进进展。尽管有充分的证据表明，雌激素代谢产物在体外和动物模型中是肿瘤的，但雌激素代谢产物可以充当遗传毒性致癌物的想法已经存在了很长时间，但仍存在争议。我们先前的研究表明，抗氧化应激酶，例如醌还原酶（QR）和谷胱甘肽S-转移酶PI，响应于乳腺上皮细胞系中的抗雌激素他莫昔芬而上调。我们进一步解剖抗氧化酶的转录调节表明，该调节涉及雌激素受体β（ER对ER的最初研究ER对雌激素诱导的DNA损伤的功能作用。通过识别雌激素诱导的DNA损害的因素，通过抑制雌激素诱导的DNA损害，我们在DNA中的作用良好，可以验证雌激素型的疾病的作用，并在DNA损害的作用中，并抑制雌激素的作用。基于我们的发现，我们假设ER酶可以防止雌激素的遗传毒性，从而阻止雌激素介导的乳腺肿瘤开始，以测试我们的假设拟议的研究应为选择性雌激素受体调节剂（SERMS）的癌症预防作用提供重要的见解。这些机械研究对于开发用于化学预防的分子靶向方法以及其他测试有希望的新药物的模型至关重要。