A CONDITIONAL MOUSE TUMOR MODEL TO STUDY CANCER AND AGIN

癌症是一种与年龄相关的疾病。在过去的十年中，癌症的发病率有所增加，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，所有癌症死亡人数的69%都在这一年龄组。老年肿瘤的发生很难研究，因为目前还没有动物模型可以比较小鼠和老年小鼠“相似”的肿瘤。在为老年人开发癌症治疗方法方面也存在类似的问题。大多数动物模型是异种移植模型，小鼠非常年轻，即6-8周。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，老年人对癌症的免疫系统激活需要其他策略，而不是年轻人。同样，已有研究表明，老年人的药物疗效和药代动力学与年轻人不同。因此，发展研究癌症的动物模型是非常重要的。这项建议的长期目标是开发一种乳腺癌小鼠模型，在该模型中，激活的neu癌基因被置于多西环素控制的反式激活因子(TTAi)系统的控制下，从而允许在年轻或老年小鼠中诱导肿瘤。为了实现这些目标，具体的目标如下：(1)建立包含两种DNA结构的双重转基因小鼠：由小鼠-乳腺-肿瘤病毒(MMTV)启动子(称为MMTV-tTAi)控制的tTAi和由四环素操纵子(Teto)和基本启动子元件Tata(称为Teto-Tata-neu)控制的激活的neu癌基因；(2)通过给药多西环素诱导年轻和老年转基因小鼠的乳腺肿瘤。这种小鼠模型将对为老年人量身定做癌症治疗方案具有重要价值，并将更普遍地用于研究癌症与衰老之间的关系。

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.