Determinants of Chemoprevention by SERMs

SERM 化学预防的决定因素

• 批准号: 7450855
• 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
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450855
• 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

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）： 虽然人们普遍认为患乳腺癌的风险与一生中暴露于雌激素直接相关，但雌激素在乳腺癌发生和发展中的确切作用尚未确定。据推测，启动可能是由于诱导进一步的DNA损伤的雌激素代谢产物与预先存在的病变，而通过雌激素受体（ER）的促有丝分裂基因的上调可能会促进进展。虽然有强有力的证据表明，雌激素代谢物在体外和动物模型中是致瘤的，但雌激素代谢物可以作为遗传毒性致癌物的想法已经存在了相当长的一段时间，但仍然存在争议。我们以前的研究表明，抗氧化应激酶，如醌还原酶（QR）和谷胱甘肽S-转移酶Pi，在乳腺上皮细胞系中响应于抗雌激素他莫昔芬而上调。我们对抗氧化酶的转录调控的进一步剖析表明，这种调控涉及雌激素受体β（ER），这是ER对抗雌激素诱导的DNA损伤的功能作用的初步研究。通过确定抑制雌激素诱导的DNA损伤的因素，我们处于一个很好的位置，以验证雌激素代谢产物在DNA损伤和乳腺肿瘤的发生，以及抗氧化应激酶预防癌症的作用。基于我们的研究结果，我们假设ER酶保护免受雌激素的遗传毒性作用，从而防止雌激素介导的乳腺肿瘤的发生。为了验证我们的假设，我们建议确定：（1）抗雌激素药物化学预防乳腺肿瘤发生的决定因素是什么？(2)QR能否抑制雌激素诱导的早期乳腺癌的发生？我们提出的研究应该提供重要的见解的基础上，选择性雌激素受体调节剂（SERM）的癌症预防作用。我们还将开发新的研究模型来测试SERM的乳腺癌化学预防潜力。这些机制研究对于开发化学预防的分子靶向方法以及开发用于测试有前途的新药剂的其他模型至关重要。