Isothiocyanate-Mediated Breast Cancer Prevention

异硫氰酸盐介导的乳腺癌预防

基本信息

批准号：
8511899
负责人：
LOUISE R HOWE
金额：
$ 8.45万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511899
关键词：
Acceleration Accounting Acetylcysteine Adverse effects Antioxidants Apoptosis Area Aromatase Inhibitors Behavior Binding Biological Biological Assay Biological Markers Bolus Infusion Breast Breast Cancer Model Breast Cancer Prevention Breast Carcinoma Broccoli - dietary Carcinogens Cardiovascular system Cell physiology Chemopreventive Agent Clinic Clinical Clinical Research Colorectal Neoplasms Consumption Coxibs Data Development Diet Dietary Component Dietary Intervention Dietary Isothiocyanate Drug Metabolic Detoxication Employee Strikes Enzyme Induction Enzymes Epidemiology Epigenetic Process Estrogen Receptors Estrogen receptor negative Estrogen receptor positive Estrogens Food Foundations Funding Future Genes Glucosinolates Glutamate-Cysteine Ligase Goals Growth Harvest Health Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Histones Human Hydrolysis In Vitro Individual Intake Intraepithelial Neoplasia Investigation Isothiocyanates Link Literature Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Mediating Metastatic Neoplasm to the Lung Modeling Molecular Target Mouse Mammary Tumor Virus Mucous Membrane Mus Myrosinase NAD(P)H Dehydrogenase (Quinone)Neoplasm Metastasis Neoplasms Nuclear Nutritional Observational Study Oncogenes Oxidants Patients Phase Phytochemical Pilot Projects Plants Plasma Population Premalignant Preventive Prophylactic treatment Prostate Recommendation Relative (related person)Research Response Elements Risk Reduction Rodent Role Selective Estrogen Receptor Modulators Source Sulforaphane Surveys System Tamoxifen Testing Therapeutic Tissues Translating Validation anticancer activity base bioactive food component cancer prevention cancer risk cruciferous vegetable cyclooxygenase 2 evidence base falls glucoraphanin heme oxygenase-1 hormone therapy improved in vivo interest malignant breast neoplasm mouse model novel overexpression pre-clinical preclinical study prevent programs promoter prophylactic public health relevance receptor expression tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The main goals of this research are to test the ability of dietary sulforaphane (SFN) to prevent "spontaneous", or oncogene-induced, breast cancer, and thereby to establish a tractable system for novel mechanistic studies of SFN-mediated breast cancer suppression. SFN is a dietary isothiocyanate derived from a precursor compound (glucoraphanin) during consumption of cruciferous vegetables such as broccoli, a particularly rich source of the SFN precursor. Consistent with the inverse relationship between cruciferous vegetable intake and breast cancer risk identified in some observational studies, SFN has potent anticancer activity in experimental breast cancer models. Specifically, SFN protects against rodent breast neoplasia induced by carcinogen treatment, most likely as a consequence of Phase II enzyme induction and resultant acceleration of carcinogen deactivation. Recently however, a novel activity has been identified for SFN as an epigenetic modulator through inhibition of histone deacetylase (HDAC) activity. Strikingly, SFN has been shown to alter histone acetylation status both in vitro and in vivo in mice and humans. Here we propose to study SFN using a carcinogen-independent or "spontaneous" breast cancer model in which estrogen receptor (ER) -negative breast neoplasia is driven by oncogene overexpression. This widely used mouse model should provide a useful experimental system in which to ultimately evaluate the importance of SFN-mediated HDAC inhibition. SFN will be delivered in the form of broccoli sprouts, an exceptionally rich source of the SFN precursor. This provides maximal translational relevance since ongoing NCI-funded trials are testing broccoli sprout SFN in patients with breast and prostate intraepithelial neoplasia. The goals of the research proposed herein are two- fold. Firstly, we will test the effect of dietary SFN on tumor formation, multiplicty, growth rate and metastasis. Secondly, we will examine SFN-mediated modulation of biological endpoints in mouse mammary tissues, using normal and precancerous breast tissues and breast carcinomas. Assays will include: HDAC activity and histone acetylation status, Phase II enzyme expression, proliferation and apoptosis. Additionally, we will compare ER expression in tumors from control and SFN-treated mice. These pilot studies will lay the foundation for future R01-scale investigations to establish causal links between observed changes and SFN- mediated tumor protection, and for investigating the utility of SFN for epigenetically restoring sensitivity of ER- negative cancers to endocrine therapy. We anticipate that data obtained from these studies will be extremely important for informing biomarker selection for clinical studies of SFN for breast cancer prophylaxis. By using broccoli sprouts we emphasize a "whole-food" approach to cancer prevention which may be pertinent in developing evidence-based health recommendations that could significantly reduce the burden of breast cancer. Our proposal is thus highly responsive to several areas of interest defined by PAR-11-079.

描述（由申请人提供）：本研究的主要目标是测试膳食萝卜硫素（SFN）预防“自发性”或癌基因诱发的乳腺癌的能力，从而建立一个易于处理的系统，用于新机制研究SFN 介导的乳腺癌抑制。 SFN 是一种膳食异硫氰酸盐，源自食用十字花科蔬菜（如西兰花）期间的前体化合物（萝卜硫苷），西兰花是 SFN 前体的特别丰富的来源。与一些观察性研究中发现的十字花科蔬菜摄入量与乳腺癌风险之间的负相关关系一致，SFN 在实验性乳腺癌模型中具有有效的抗癌活性。具体来说，SFN 可以预防由致癌物治疗引起的啮齿动物乳腺肿瘤，这很可能是 II 期酶诱导和由此加速致癌物失活的结果。然而最近，SFN 通过抑制组蛋白脱乙酰酶 (HDAC) 活性而被鉴定为表观遗传调节剂。引人注目的是，SFN 已被证明可以在小鼠和人类的体外和体内改变组蛋白乙酰化状态。在这里，我们建议使用不依赖致癌物或“自发性”乳腺癌模型来研究 SFN，其中雌激素受体 (ER) 阴性乳腺肿瘤是由癌基因过度表达驱动的。这种广泛使用的小鼠模型应该提供一个有用的实验系统，最终评估 SFN 介导的 HDAC 抑制的重要性。 SFN 将以西兰花芽的形式提供，西兰花芽是 SFN 前体的极其丰富的来源。这提供了最大的转化相关性，因为正在进行的 NCI 资助的试验正在测试西兰花芽 SFN 对乳腺癌和前列腺上皮内瘤变患者的作用。本文提出的研究目标有两个。首先，我们将测试膳食SFN对肿瘤形成、增殖、生长速度和转移的影响。其次，我们将使用正常和癌前乳腺组织以及乳腺癌来检查 SFN 介导的小鼠乳腺组织生物学终点的调节。检测包括：HDAC 活性和组蛋白乙酰化状态、II 期酶表达、增殖和凋亡。此外，我们将比较对照小鼠和 SFN 治疗小鼠肿瘤中 ER 的表达。这些试点研究将为未来的 R01 规模研究奠定基础，以建立观察到的变化与 SFN 介导的肿瘤保护之间的因果关系，并研究 SFN 在表观遗传上恢复 ER 阴性癌症对内分泌治疗敏感性的效用。我们预计从这些研究中获得的数据对于为临床研究的生物标志物选择提供极其重要的信息 SFN 用于乳腺癌预防。通过使用西兰花芽，我们强调“全食物”预防癌症的方法，这可能有助于制定基于证据的健康建议，从而显着减轻乳腺癌的负担。因此，我们的提案高度响应了 PAR-11-079 定义的几个感兴趣的领域。