Oncogeneses and Retinoid Chemoprevention

致癌和类维生素A化学预防

基本信息

批准号：
7459636
负责人：
Eduardo F Farias
金额：
$ 29.21万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-09 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7459636
关键词：
Acute Promyelocytic Leukemia Address Agonist Am 580 Am 80 Anabolism Attention Automobile Driving Binding Proteins Breast Breast Cancer Model Cancer Etiology Cell Differentiation process Cells Cellular Retinol Binding Protein Chemoprevention Clinical Trials Confidence Intervals Data Development Differentiation and Growth Disease Disease remission Dose Down-Regulation E-Cadherin Effectiveness of Interventions Epithelial Cells Estrogen receptor negative Etiology Event FVB/N Mouse Female Gene Expression Gene Silencing Genes Goals Growth Human Hypermethylation Incidence Intervention Link MYC Family Genes Malignant Neoplasms Mammary Neoplasms Mammary gland Methylation Modeling Mouse Mammary Tumor Virus Mus Nutrient Oncogenes Oncogenic Outcome Pathway interactions Pharmaceutical Preparations Preventive Protein Isoforms Protein Overexpression Proteins Receptor Gene Receptor Inhibition Reporting Research Personnel Retinoic Acid Receptor Retinoids Retinol Binding Proteins Role Secondary Cancer Prevention Signal Transduction Site T47D Testing Time Tissue Sample Transgenic Mice Transgenic Organisms Translating Tretinoin Vitamin A Woman base cancer prevention concept contextual factors design dietary supplements gene function malignant breast neoplasm mammary epithelium mouse model neoplastic cell prevent promoter retinoic acid receptor alpha success tumor tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): Our long term goal is to understand the role in breast cancer of retinoic acid receptor (RAR) genes and genes that function upstream of RAR to regulate vitamin A storage and retinoic acid biosynthesis, in particular the cellular retinol-binding protein 1 gene (CRBP1). The rationale for this goal is the growth suppressive and differentiation-inducive activities of RARs and the downregulation in breast cancer of RAR isoforms and CRBP1, Using transgenic mouse models that are relevant to human breast cancer, we found that RARs modulate tumor incidence in an oncogene-specific manner. Our data predict that retinoid intervention will be beneficial or counterproductive depending on the oncogenic pathway driving transformation. In Aim 1, we will test our specific hypothesis that treatment of mammary tumor-prone MMTV- Neu females with retinoid (Am580/Am80) will accelerate tumor development whereas the same treatment of mammary tumor-prone MMTV-Wnt1 and MMTV-Myc females will delay tumor development. In related studies, we found that CRBP1 promotes vitamin A storage in breast tumor epithelial cells and positively regulates RAR activity; in turn, RAR inhibits the PI3K/Akt survival pathway promoting tumor cell differentiation and growth inhibition. Therefore, CRBP1 links cellular uptake and storage of a dietary nutrient, vitamin A, to cell differentiation and growth suppression. We found that, just as in human breast cancer, CRBP1 is downregulated in the MMTV-Myc mouse model of breast cancer. In Aim 2, we will study MMTV- Myc transgenic mice to test whether loss of CRBP1 expression is a causal event that precedes tumor formation. In Aim 3, we will generate MMTV-CRBP1 transgenic mice and cross these to MMTV-Myc mice to test whether ectopic CRBP1 expression prevents tumor formation by Myc. New preventive drugs are needed for women with early estrogen receptor negative breast cancer. We propose that selective retinoids can be effective but only when the disease is associated with specific cancer causing genes (it may otherwise prove deleterious). If our concept is validated, it will guide the design of retinoid clinical trials. We will also critically address the relevance of a vitamin A-binding protein that is lost in breast cancer. We believe that this protein defines whether breast cells can use vitamin A and that its loss contributes to disease causation or progression.

描述（由申请人提供）：我们的长期目标是了解视黄酸受体（RAR）基因和在 RAR 上游发挥作用的基因在乳腺癌中的作用，以调节维生素 A 储存和视黄酸生物合成，特别是细胞视黄醇 -结合蛋白 1 基因 (CRBP1)。这一目标的基本原理是 RAR 的生长抑制和分化诱导活性以及 RAR 亚型和 CRBP1 在乳腺癌中的下调。使用与人类乳腺癌相关的转基因小鼠模型，我们发现 RAR 调节癌基因中的肿瘤发生率- 具体方式。我们的数据预测，视黄醇干预将是有益的还是适得其反的，具体取决于驱动转化的致癌途径。在目标 1 中，我们将检验我们的具体假设，即用类视黄醇 (Am580/Am80) 治疗易患乳腺肿瘤的 MMTV-Neu 女性将加速肿瘤的发展，而对易患乳腺肿瘤的 MMTV-Wnt1 和 MMTV-Myc 女性进行相同的治疗将加速肿瘤的发展。延缓肿瘤的发展。在相关研究中，我们发现CRBP1促进乳腺肿瘤上皮细胞维生素A储存，并正向调节RAR活性；反过来，RAR 抑制 PI3K/Akt 存活途径，促进肿瘤细胞分化和生长抑制。因此，CRBP1 将细胞对膳食营养素维生素 A 的吸收和储存与细胞分化和生长抑制联系起来。我们发现，与人类乳腺癌一样，CRBP1 在 MMTV-Myc 小鼠乳腺癌模型中表达下调。在目标 2 中，我们将研究 MMTV-Myc 转基因小鼠，以测试 CRBP1 表达缺失是否是肿瘤形成之前的因果事件。在目标 3 中，我们将生成 MMTV-CRBP1 转基因小鼠，并将其与 MMTV-Myc 小鼠杂交，以测试异位 CRBP1 表达是否阻止 Myc 形成肿瘤。患有早期雌激素受体阴性乳腺癌的女性需要新的预防药物。我们认为，选择性类视黄醇可能有效，但前提是该疾病与特定的致癌基因相关（否则可能是有害的）。如果我们的概念得到验证，它将指导类维生素A临床试验的设计。我们还将批判性地探讨乳腺癌中丢失的维生素 A 结合蛋白的相关性。我们相信，这种蛋白质决定了乳腺细胞是否可以利用维生素 A，并且它的损失会导致疾病的因果关系或进展。