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 B-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 murine 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.