MOUSE MODELS OF HUMAN BREAST CANCER

这项提议的长期目标是开发更接近人类乳腺癌的小鼠模型。这将通过将多个突变引入乳腺上皮细胞亚群来实现。研究人员将研究新的基因工程技术，利用插入β -酪蛋白基因的Cre，以可复制的方式创造出能够在乳腺中表现出靶向基因激活或基因缺失的小鼠。然后将表达cre的小鼠与含有loxP位点的小鼠进行杂交，从而激活致癌基因或使肿瘤抑制基因失活。这项技术的成功开发和实施应该适用于任何对乳腺感兴趣的基因，并在适当的启动子下适用于其他器官部位。这项技术将应用于开发复制人类乳腺癌主要亚群显著特征的小鼠模型。这些海洋模型将包括条件Brca2和p53等位基因，诱导型c-myc和p53 172 arg-his突变体以及构成型p53纯合无基因。不同的模型将检查人类乳腺癌的显著特征，包括早期发病机制表现为导管内增生，乳腺肿瘤发生的风险增加，自发的和由于化学致癌物质、辐射和雌激素治疗的结果；遗传不稳定导致基因表达的进行性改变，转移到外周器官，以及至少一部分肿瘤，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群，并敏感地预测对化学预防和治疗药物的反应，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.