DMBA诱发高脂饮食模式树鼩乳腺癌模型的比较代谢组学分析

Breast cancer has become the number one malignant tumor injurious to female health in the late 1990s. Research indicates that the incidence of breast cancer has shown a marked increasing trend in China in recent years, and high-fat diet may increase breast cancer risk. At present, people’s knowledge of breast cancer comes mainly from laboratory rats and mice, but it is difficult to simulate the hallmarks of human breast cancer in such laboratory rats and mice, so it is hard to implement translational medicine research in animal experiments, and thereby cannot increase the success rate of translational medicine. A breast cancer animal model built of an appropriate non-human primate may play an important role in increasing the success rate of translational breast cancer medicine research. This project is to select female laboratory tree shrew and keep it with high-fat feed according to the contemporary high-fat diet style, use DMBA to induce the breast cancer model for plasma metabonomics detection, and compare it with the detection result of plasma metabonomics in the clinical patients with breast cancer, to evaluate the similarity between the tree shrew breast cancer model and human breast cancer, to investigate the value of tree shrew as a human breast cancer model animal, so as to provide a scientific theoretical basis for more effective prevention of breast cancer.

乳腺癌从上世纪90年代后期就已成为危及女性健康的恶性肿瘤的第1位。研究表明，近年来我国乳腺癌的发病率出现明显的上升趋势，高脂饮食方式可增加患乳腺癌的风险。目前人们对乳腺癌的认识主要依赖于实验大鼠和小鼠，但是这类实验大鼠和小鼠很难模拟成人类乳腺癌的特性，使动物实验很难实现转化医学研究，形成提高转化医学成功率的瓶颈。选用一种适当的非人灵长类动物建立乳腺癌动物模型，对于提高乳腺癌的转化医学研究成功率将起着重要的作用。本项目拟选用雌性实验树鼩，模拟现代人高脂饮食方式用高脂饲料饲养，用DMBA诱发乳腺癌模型，进行血浆代谢组学检测，并与临床乳腺癌病人的血浆代谢组学检测结果进行比较，评价树鼩乳腺癌模型与人类乳腺癌的相似性，探讨树鼩作为人类乳腺癌模型动物的价值，为更好地开展乳腺癌防治工作提供科学理论依据。

乳腺癌居女性恶性肿瘤的首位，已成为社会的重大公共卫生问题。本项目模拟现代人高脂饮食的不良生活方式，采用高脂饲料饲养树鼩，用化学致癌因素诱发树鼩乳腺癌模型，分析树鼩乳腺癌的代谢组学变化，与临床乳腺癌病人进行比较代谢组学分析，为更好地开展乳腺癌防治工作提供科学理论依据。.研究内容：①诱发实验动物乳腺癌模型：高脂饲料喂养，用DMBA 溶液对SPF级雌性Wistar大鼠和清洁级雌性树鼩灌胃诱发乳腺癌模型；②乳腺癌大鼠和乳腺癌树鼩血清样本代谢组学检测。项目执行过程中增加了对自发性乳腺癌树鼩的血清代谢组学检测；③临床乳腺癌病人血清代谢组学检测，同时增加了对临床乳腺癌患者血浆中鞘脂组分析。.研究结果：① 对乳腺癌大鼠代谢组学检测共鉴定到7种差异表达代谢物，富集到5条显著的信号通路中，按显著性大小依次为：氨基酸生物合成、2-羰基羧酸代谢、缬氨酸代谢、亮氨酸和异亮氨酸的生物合成、ABC转运蛋白代谢；② 对乳腺癌树鼩代谢组学检测共鉴定到18种差异表达代谢物，富集到7条显著的信号通路中，按显著性大小依次为：乙醛酸和二甲酰化代谢、柠檬酸循环、精氨酸和脯氨酸代谢、丙氨酸代谢、天冬氨酸和谷氨酸代谢、鞘脂代谢、缬氨酸代谢、亮氨酸和异亮氨酸降解、嘌呤代谢；③ 对自发性乳腺癌树鼩代谢组学检测共鉴定到14种差异表达代谢物，核糖酸，γ-内酯代谢物浓度显著上升，脯氨酸、苏氨酸、丝氨酸、花生四烯酸、肌酸等13种代谢物浓度显著下降，花生四烯酸代谢、精氨酸和脯氨酸代谢3个代谢通路发生显著改变；④ 对临床乳腺癌病人代谢组学检测共鉴定到12种差异表达代谢物，关联的信号通路有精氨酸和脯氨酸代谢，烟酸和烟酰胺代谢，D-精氨酸和D-鸟氨酸代谢。.对临床乳腺癌病人血浆中鞘脂组分析有待进一步进行，相关的血清代谢组学检测结果有待进一步进行比较代谢组学分析，最终研究结果可对于临床乳腺癌防治提供相应的理论参考依据。