Identification of Mechanisms of Cannellini Bean Effects on Breast Cancer

描述（由申请人提供）：本提案基于我们对化学诱导的非肥胖乳腺癌大鼠模型的初步研究，在该模型中，食用煮熟的cannellini bean(一种独特的普通豆（Phaseolus vulgaris L.），可将乳腺癌发病率降低70%，肿瘤多样性降低3倍，肿瘤质量降低5倍。总体假设地中海饮食中常见的Cannellini豆通过对肥胖相关胰岛素抵抗、慢性炎症和外周芳香化的系统性影响以及直接通过影响致癌的细胞信号网络发挥乳腺癌抑制活性。该实验将使用1)化学诱导、肥胖敏感或耐药的乳腺癌大鼠模型，这些模型在HR受体状态和HER2/Neu表达方面存在明显差异，或者2)乳腺上皮细胞中mtor相关信号通路失调的小鼠模型。目的1。该假设的基本原理是，Cannellini豆通过激活LKB1/AMPK/raptor和SIRT1信号节点，通过胰岛素/IGF-1途径和细胞内信号通路减少信号，并诱导TSC1/2抑制因子活性，从而抵消mTOR去调控的影响，从而系统性地发挥作用。对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下游靶点S6kinase、4E-BP1和FOXO3a。目标2。假设：意大利面豆喂养抑制肥胖相关的外周芳香化。其基本原理是，喂养cannellini bean可改善胰岛素敏感性，减少慢性炎症，激活LKB1/AMPK轴，从而抑制外周芳构化和肿瘤发展。目标3。假设：Cannellini豆喂养抑制肿瘤内新生脂质合成新生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，缩小肿瘤大小，与观察到的Cannellini对乳腺癌发生的作用一致。工作将集中在识别与肿瘤快速生长相关的脂质合成关键调控节点的改变。这些分析将通过评估与肿瘤侵袭性相关的膜磷脂成分来补充。对脂质代谢影响的假设起源包括mtor相关信号的下调和慢性炎症的抑制。

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.