MOUSE MODELS OF HUMAN BREAST CANCER

这项提议的长期目标是开发更接近于人类乳腺癌的小鼠模型。这将通过在乳腺上皮细胞的子集中引入多个体细胞突变来实现。将研究新的基因工程技术，利用插入到β-酪蛋白基因中的Cre，以可重复性的方式创造出具有靶向基因激活或乳腺基因缺失的小鼠。然后，表达Cre的小鼠将与含有loxP位点的小鼠杂交，这些小鼠被设计成要么导致癌基因的激活，要么导致肿瘤抑制基因的失活。这项技术的成功开发和实施应该适用于任何与乳腺相关的基因，并在适当的启动子的作用下，适应于其他器官部位。这项技术将被应用于开发复制人类乳腺癌主要亚型显著特征的小鼠模型。这些海洋模型将包括条件性BRCA2和P53等位基因、可诱导的c-myc和P53 172 Arg-His突变体以及结构性的P53纯合缺失。不同的模型将研究人类乳腺癌的显著特征，包括表现为导管内增生的早期发病机制，乳腺癌发生的风险增加，这既是自发的，也是化学致癌物、辐射和雌激素治疗的结果；导致基因表达进行性变化的遗传不稳定，转移到外围器官，以及至少一种肿瘤的亚组，卵巢激素依赖。这样的模型应该更准确地模拟人类乳腺癌的亚型，是对化学预防和治疗药物反应的敏感预测因子，以及识别肿瘤发展和肿瘤进展的后续变化的模型。

The long-term objective of this proposal is to develop mouse models that more closely mimic human breast cancer. This will be accomplished by introducing multiple mutations somatically into a subset of mammary epithelial cells. New genetic engineering technologies will be investigated to create mice that exhibit targeted gene activation or deletion of genes in the mammary gland in a reproducible manner using Cre inserted into the beta- casein gene. Cre-expressing mice will then be bred with mice containing loxP sites engineered to result in either the activation of oncogenes or the inactivation of tumor suppressor genes. The successful development and implementation of this technology should be applicable to any gene of interest for the mammary gland and adaptable, with appropriate promoters, to other organ sites. This technology will be applied to develop mouse models that replicate salient features of major subsets of human breast cancer. These marine models will include conditional Brca2 and p53 alleles, inducible c-myc and p53 172 arg-his mutant as well as constitutive p53 homozygous nulls. The different models will be examined for salient features of human breast cancer that include an early pathogenesis exhibiting intraductal hyperplasia, enhanced risks for mammary tumorigenesis, both spontaneous and as a consequence of treatment with chemical carcinogens, irradiation and estrogens; genetic instability that results in progressive changes in gene expression, metastases to peripheral organs, and for at least a subset of tumors, ovarian- hormone dependence. Such models should more accurately mimic subsets of human breast cancer and be sensitive predictors of response to chemopreventive and therapeutic agents as well as models to identify subsequent alterations in neoplastic development and tumor progression.