A CONDITIONAL MOUSE TUMOR MODEL TO STUDY CANCER AND AGIN

癌症是一种与年龄有关的疾病。癌症的发病率在过去十年中有所增加，主要是由于老年人口的增加。目前，60%的恶性肿瘤发生在65岁及以上的年龄组，69%的癌症死亡发生在这个年龄组。老年时的肿瘤发生很难研究，因为没有动物模型可以比较年轻和年老小鼠的“相似”肿瘤。类似的问题也存在于针对老年人的癌症疗法的开发中。大多数使用的动物模型是非常年轻的小鼠，即6-8周的异种移植模型。然而，老年人对疫苗或药物治疗的反应与年轻人不同。与年龄相关的t细胞反应性下降表明，与年轻人相比，老年人激活免疫系统对抗癌症需要其他策略。同样，研究表明，药物在老年人中的疗效和药代动力学与年轻人不同。因此，建立动物模型来研究青年和老年癌症是很重要的。这项提议的长期目标是建立一种乳腺癌小鼠模型，其中激活的新癌基因置于强力霉素控制的反激活物（tTAi）系统的控制下，允许在年轻或年老小鼠中诱导肿瘤。为了实现这些目标，具体目标如下：(1)开发含有两种DNA结构的双转基因小鼠：由小鼠乳腺肿瘤病毒（MMTV）启动子控制的tTAi（称为MMTV-tTAi）和由四环素操纵子（TetO）和基础启动子元件TATA（称为TetO-TATA-neu）控制的活化的新癌基因；(2)给药强力霉素诱导年轻和年老转基因小鼠乳腺肿瘤。这一小鼠模型对于为老年人量身定制癌症治疗方案具有重要价值，对于研究癌症与衰老之间的关系具有更广泛的意义。

Cancer is an age-related disease. The frequency of cancer has increased over the last decade, mainly due to an increase in the elderly population. Currently, 60 percent of all malignant tumors occur in the age group of 65 years and older and 69 percent of all cancer deaths are in this group. Tumorigenesis at old age is difficult to study, because there are no animal models available allowing the comparison of "similar" tumors in young and old mice. A similar problem exists in the development of cancer therapies for the elderly. Most animal models used are xenograft models with very young mice, i.e., 6-8 weeks. However, the elderly react differently to vaccine or drug therapies than young people. Age-related decline in T-cell responsiveness suggests that activation of the immune system against cancer in the elderly needs other strategies than in young adults. Similarly, it has been shown that the efficacy and pharmacokinetics of drugs in the elderly is different from young adults. Therefore, it is important to develop animal models to study cancer at young and old age. The long-term objective of this proposal is to develop a mouse model for breast cancer in which an activated neu oncogene is placed under the control of the doxycycline-controlled transactivator (tTAi) system, permitting tumor induction in either young or old mice. To achieve these goals the specific aims are as follows: (1) develop dual transgenic mice containing two DNA constructs: tTAi under control of a mouse-mammary-tumor virus (MMTV) promoter (called MMTV-tTAi), and the activated neu oncogene under the control of a tetracycline operon (TetO) and basal promoter element TATA (called TetO-TATA-neu); and (2) induction of mammary gland tumors in young and old transgenic mice by administration of doxycycline. This mouse model will be of great value for tailoring cancer therapies to the elderly and will be more generally useful to study the relationship between cancer and aging.