Identification of Mechanisms of Cannellini Bean Effects on Breast Cancer

鉴定 Cannellini 豆对乳腺癌的作用机制

• 批准号: 8852569
• 负责人: Henry J Thompson
• 金额: $ 30.86万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852569
• 关键词: Acetyl-CoA Carboxylase; Adipose tissue; Affect; American; Androgens; Attenuated; Biological Markers; Breast Cancer Model; Breast Epithelial Cells; Cancer Burden; Carcinoma; Characteristics; Chronic; Coenzyme A; Comorbidity; Complement; Consumption; Data; Development; Diabetes Mellitus; Dissection; Dose; Down-Regulation; ERBB2 gene; Eating; Estrogens; Fatty-acid synthase; Flavonoids; Food; Genetic; Health; Hormone Receptor; Human; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intake; Knock-out; Link; Lipids; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediterranean Diet; Membrane; Metformin; Micronutrients; Modeling; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oncogene Deregulation; Oncogenes; Outcome; Oxidoreductase; PTEN gene; Pathway interactions; Pattern; Peripheral; Phaseolus vulgaris; Phospholipids; Phosphorylation; Plasma; Population; Postmenopause; Prevalence; Proteins; Publishing; Raptors; Rattus; Regulation; Reporting; Resistance; Risk; Rodent; SRE-1 binding protein; STK11 gene; Signal Transduction; Site; Source; Stearoyl-CoA Desaturase; Suppressor Genes; TSC1/2 gene; TSC2 gene; Tissues; United States; Woman; Work; base; bean; cancer risk; carcinogenesis; cooking; feeding; improved; insulin sensitivity; lipid biosynthesis; lipid metabolism; mTOR protein; malignant breast neoplasm; mammary epithelium; metabolomics; mortality; mouse model; oxidation; population based; pre-clinical; prospective; receptor; research study; tumor; tumor growth

DESCRIPTION (provided by applicant): This proposal is based on our preliminary studies in a chemically-induced non-obese rat model for breast cancer in which consumption of cooked cannellini bean, a distinct variety of common bean (Phaseolus vulgaris L.), reduced breast cancer incidence by 70%, tumor multiplicity by 3-fold, and tumor mass by 5-fold. Overall hypothesis Cannellini bean, common in Mediterranean diets, exerts breast cancer inhibitory activity by systemic effects on obesity associated insulin resistance, chronic inflammation, and peripheral aromatization and directly via effects on cell signaling networks that affect carcinogenesis. Specific Aims The proposed experiments will use either 1) chemically induced, obesity sensitive or resistant rat models for breast cancer with well characterized differences in HR receptor status and HER2/Neu expression, or 2) a mouse model in which mTOR-related signaling is deregulated in mammary epithelial cells. Aim 1. Hypothesis: Cannellini bean feeding attenuates deregulated mTOR signaling The rationale for this aim is that cannellini bean exerts effects systemically by reducing signaling via the insulin/IGF-1 pathway and intracellularly by activating LKB1/AMPK/raptor and SIRT1 signaling nodes and induces TSC1/2 repressor activity which counteract the effects of mTOR de-regulation. Dissection of the mechanisms of mTOR network regulation will focus on site specific phosphorylations of TSC2, PRAS40, Akt, LKB1, AMPK and raptor as well as assessing mTOR downstream targets S6kinase, 4E-BP1, and FOXO3a. Aim 2. Hypothesis: Cannellini bean feeding inhibits obesity-associated peripheral aromatization. The underlying rationale is that feeding cannellini bean improves insulin sensitivity, decreases chronic inflammation, and activates the LKB1/AMPK axis, thereby suppressing peripheral aromatization and tumor development. Aim 3. Hypothesis: Cannellini bean feeding inhibits de novo intra-tumoral lipid synthesis De novo lipid synthesis is a universal characteristic in breast cancer and inhibition of lipid synthesis would be expected to delay tumor occurrence and reduce tumor size, consistent with observed effects of cannellini on mammary carcinogenesis. Work will concentrate on identifying alterations in key regulatory nodes in lipid synthesis associated with rapid tumor growth. These analyses will be complemented by assessment for membrane phospholipid constituents linked to tumor aggressiveness. Hypothesized origins of effects on lipid metabolism include down regulation of mTOR-related signaling and suppression of chronic inflammation.

描述（由申请人提供）：该提案基于我们对化学诱导的非肥胖大鼠乳腺癌模型的初步研究，在该模型中，食用煮熟的cannellini豆（一种独特的普通豆类（Phaseolus vulgaris L.））可将乳腺癌发病率降低70%，肿瘤多重性降低3倍，肿瘤质量降低5倍。总体假设 Cannellini 豆在地中海饮食中很常见，它通过对与肥胖相关的胰岛素抵抗、慢性炎症和外周芳香化产生系统性影响，以及直接通过对影响致癌作用的细胞信号网络的影响来发挥乳腺癌抑制活性。具体目标拟议的实验将使用 1) 化学诱导的、肥胖敏感或耐药的乳腺癌大鼠模型，在 HR 受体状态和 HER2/Neu 表达方面具有明确的差异，或 2) 乳腺上皮细胞中 mTOR 相关信号传导失调的小鼠模型。目标 1. 假设：cannellini 豆喂养会减弱 mTOR 信号传导失调 该目标的基本原理是，cannellini 豆通过减少胰岛素/IGF-1 途径的信号传导以及通过激活 LKB1/AMPK/raptor 和 SIRT1 信号节点在细胞内发挥全身作用，并诱导 TSC1/2 阻遏物活性，从而抵消 mTOR 的影响 放松管制。 mTOR 网络调控机制的剖析将重点关注 TSC2、PRAS40、Akt、LKB1、AMPK 和 raptor 的位点特异性磷酸化，以及评估 mTOR 下游靶标 S6kinase、4E-BP1 和 FOXO3a。目标 2. 假设：Cannellini 豆喂养抑制与肥胖相关的外周芳香化。其基本原理是，喂养cannellini豆可以提高胰岛素敏感性，减少慢性炎症，并激活LKB1/AMPK轴，从而抑制外周芳香化和肿瘤发展。目标 3. 假设：Cannellini 豆喂养抑制从头肿瘤内脂质合成从头脂质合成是乳腺癌的普遍特征，抑制脂质合成有望延缓肿瘤发生并减小肿瘤大小，这与观察到的 cannellini 对乳腺癌发生的作用一致。工作将集中于识别与肿瘤快速生长相关的脂质合成关键调节节点的变化。这些分析将通过与肿瘤侵袭性相关的膜磷脂成分的评估来补充。脂质代谢影响的假设来源包括 mTOR 相关信号传导的下调和慢性炎症的抑制。