Identification of Mechanisms of Cannellini Bean Effects on Breast Cancer

描述（由申请人提供）：该建议基于我们在化学诱导的非肥胖大鼠乳腺癌模型中的初步研究，其中食用煮熟的cannellini豆，一种不同种类的普通豆（菜豆L.），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Cannellini豆，常见于地中海饮食中，通过对肥胖相关胰岛素抵抗、慢性炎症和外周芳构化的全身作用以及直接通过对影响致癌作用的细胞信号传导网络的作用来发挥乳腺癌抑制活性。具体目的所提出的实验将使用1）化学诱导的、肥胖症敏感或抵抗的乳腺癌大鼠模型，其具有HR受体状态和HER2/Neu表达的良好表征的差异，或2）其中mTOR相关信号在乳腺上皮细胞中失调的小鼠模型。目标1。假设：该目的的基本原理是，卡涅里尼豆通过减少经由胰岛素/IGF-1途径的信号传导而全身性地发挥作用，并且通过激活LKB 1/AMPK/raptor和SIRT 1信号传导节点而在细胞内发挥作用，并诱导TSC 1/2阻遏物活性，其抵消mTOR失调的作用。mTOR网络调节机制的剖析将集中在TSC 2、PRAS 40、Akt、LKB 1、AMPK和raptor的位点特异性磷酸化，以及评估mTOR下游靶点S6激酶、4E-BP 1和FOXO 3a。目标二。假设：Cannellini豆喂养抑制肥胖相关的外周芳构化。其基本原理是，喂养cannellini豆改善胰岛素敏感性，减少慢性炎症，并激活LKB 1/AMPK轴，从而抑制外周芳构化和肿瘤发展。目标3：假设：Cannellini豆喂养抑制从头肿瘤内脂质合成从头脂质合成是乳腺癌的普遍特征，并且预期抑制脂质合成可延迟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。工作将集中在确定与快速肿瘤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来源包括下调mTOR相关信号传导和抑制慢性炎症。

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.