乳腺癌树鼩模型的建立和评价

Breast cancer is a common malignant tumor in women. It is essential to develop suitable animal models for developing novel preventive and therapeutic methods.Currently, rodents were widely used for breast cancer in vivo research. However, rodents are far away from human beings in evolution so that many pre-clinical research results from rodents could not be reproduced in the clinic. Tree shrews (Tupaia Belangeri Chinensis) have a closer evolutionary relationship with human being compared to rodents and have been successful used to eastablish animal models of hepatocellular carcinomas. We found that tree shrews develop spontaneous breast tumors with a high frequency so that they may be suitable for eastablishing novel breast cancer animal models. This project will focus on the eastablishment of tree shrew breast cancer models through two approaches: 1) Chemical carcinogens and sexual hormones; 2) Lentiviruses overexpressing oncogenes. We will study the mechanism and drug reaction during the development of tree shrew breast cancer. This project will establish novel animal models for developing novel preventive and therapeutic approaches for breast cancer.

乳腺癌是严重危害女性健康的常见恶性肿瘤。建立合适的乳腺癌实验动物模型对于研究人类乳腺癌的防治方法起着非常重要的作用。目前乳腺癌体内研究多采用啮齿类动物模型。但是啮齿类动物与人的亲缘关系比较远，导致很多实验结果在人体内无法重复。树鼩相比啮齿类在进化层次上更接近于人，并已成功建立肝癌模型 。我们在饲养和繁殖过程中发现树鼩频繁自发乳腺癌，表明树鼩可能适合建立新的乳腺癌动物模型。本项目旨在通过不同的方案(1、致癌剂和性激素；2、慢病毒过度表达癌基因)在树鼩中诱发乳腺癌。在此基础上，我们将进一步研究树鼩乳腺肿瘤产生过程中的分子机制和药效反应。本项目的完成将为乳腺癌的防治提供新的实验动物模型和研究对策。

乳腺癌是严重危害女性健康的常见恶性肿瘤, 建立合适的乳腺癌实验动物模型对于研究人类乳腺癌的防治方法起着非常重要的作用。现有针对乳腺癌的体内模型主要是啮齿类动物模型。但是啮齿类动物与人的亲缘关系比较远，导致很多实验结果在人体临床实验中无法重复。在此我们选择进化层次上更接近于人的树鼩构建适宜的乳腺癌动物模型，以期为乳腺癌的防治提供新的策略。首先我们采用DMBA灌胃并联合MPA诱导的方法成功建立了树鼩的乳腺肿瘤模型，所诱导的导管内乳头状瘤和浸润性导管癌均为人类共有的肿瘤类型，这些诱发肿瘤和树鼩自发肿瘤在病理和遗传方面比较一致。同时发现在该模型中PTEN/PIK3CA基因频繁突变可能是导致树鼩乳腺肿瘤发生的遗传基础。但是该模型存在潜伏期长、诱导效率低等缺陷。在此基础上通过慢病毒在树鼩乳腺导管内过表达癌基因PyMT高效快速的诱发出树鼩乳腺肿瘤。慢病毒过表达PyMT诱导的树鼩乳腺癌模型具有成瘤快，潜伏时间短，成瘤率高的优势。化疗药物表阿霉素和顺铂显著抑制肿瘤的生长，表明慢病毒过表达PyMT模型是潜在的药物研究和评价的模型。