A CONDITIONAL MOUSE TUMOR MODEL TO STUDY CANCER AND AGIN

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.