Identification of Mechanisms of Cannellini Bean Effects on Breast Cancer

描述(申请人提供)：这项建议是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，食用煮熟的四季豆，一种不同种类的菜豆，可将乳腺癌发病率降低70%，肿瘤多样性降低3倍，肿瘤体积减少5倍。总体而言，地中海饮食中常见的甘利尼豆通过全身作用于肥胖相关的胰岛素抵抗、慢性炎症和外周芳香化，并直接通过影响致癌的细胞信号网络发挥抑制乳腺癌的活性。具体目的建议的实验将使用1)化学诱导、肥胖敏感或耐药的乳腺癌大鼠模型，这些模型具有明确的HR受体状态和HER2/Neu表达差异的特征，或者2)mTOR相关信号在乳腺上皮细胞中被解除调控的小鼠模型。目的1.假说：小菜豆喂养可减弱mTOR信号失控，其基本原理是小菜豆通过胰岛素/IGF-1途径减少信号转导，在细胞内通过激活LKB1/AMPK/Raptor和SIRT1信号节点发挥作用，并诱导TSC1/2抑制因子活性，从而抵消mTOR信号失控的影响。对mTOR网络调控机制的剖析将集中在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S6kinase4E-BP1和FOXO3a。目的2.假设：喂食甘利尼豆能抑制肥胖相关的外周芳构化。其基本原理是，喂食意大利扁豆可以改善胰岛素敏感性，减少慢性炎症，并激活LKB1/AMPK轴，从而抑制外周芳构化和肿瘤的发展。目的3.假说：豆角抑制肿瘤内脂肪合成是乳腺癌的普遍特征，抑制脂肪合成有望延缓肿瘤的发生和缩小肿瘤体积，这与观察到的脂肪合成在乳腺癌发生中的作用一致。工作将集中于确定与肿瘤快速生长相关的脂质合成中关键调控节点的变化。这些分析将得到与肿瘤侵袭性相关的膜磷脂成分评估的补充。对脂质代谢影响的假说来源包括下调mTOR相关信号和抑制慢性炎症。

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.