Oncogeneses and Retinoid Chemoprevention

致癌和类维生素A化学预防

• 批准号: 7145010
• 负责人: Eduardo F Farias
• 金额: $ 30.09万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/7145010
• 关键词: breast neoplasms; chemoprevention; genes; model; neoplasm /cancer; retinoids

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在RAR上游起作用的视黄酸受体（RAR）基因（RAR）基因和基因的作用，以调节维生素A储存和视黄酸生物合成，尤其是细胞性视黄醇结合蛋白1基因（CRBP1）。该目标的基本原理是使用与人类乳腺癌相关的转基因小鼠模型的RAR和RAR同工型和CRBP1的乳腺癌的抑制和分化诱导活性，我们发现RARS在致癌基因特异性方式中调节了肿瘤的发生。我们的数据预测，视视网膜类似的干预将根据驱动转化的致癌途径而有益或适得其反。在AIM 1中，我们将测试我们的具体假设，即用类维生素类动物（AM580/AM80）对乳腺肿瘤的MMTV-NEU女性进行治疗将加速肿瘤的发育，而同样对乳腺肿瘤的MMTV-WNT1和MMTV-MYC女性的治疗也会延迟肿瘤的发育。在相关研究中，我们发现CRBP1促进乳腺肿瘤上皮细胞中的维生素A储存，并积极调节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将饮食营养素A的细胞摄取和储存与细胞分化和抑制作用联系起来。我们发现，就像在人类乳腺癌中一样，CRBP1在乳腺癌的MMTV-MYC小鼠模型中被下调。在AIM 2中，我们将研究MMTV-MYC转基因小鼠，以测试CRBP1表达的丧失是否是肿瘤形成之前的因果事件。在AIM 3中，我们将生成MMTV-CRBP1转基因小鼠，并将其越过MMTV-MYC小鼠，以测试异位CRBP1表达是否可以防止MYC形成肿瘤。早期雌激素受体负性乳腺癌的女性需要新的预防药物。我们建议选择性类维生素类动物可以有效，但只有当该疾病与特定癌症相关时，否则可能证明是有害的）。如果我们的概念得到验证，它将指导性类维生素类似临床试验的设计。我们还将批判性地解决乳腺癌中失去的维生素A结合蛋白的相关性。我们认为，该蛋白质定义了乳腺细胞是否可以使用维生素A，其损失有助于疾病因果关系或进展。