Breast cancer is the most common malignancy diagnosed among women in United States and is the second leading cause of cancer mortality. Despite intensive efforts aimed at improving the early detection and treatment of this disease, mortality due to breast cancer remains high. Consequently, strategies aimed at a more thorough understanding of the biology of this disease are needed. A cardinal feature of mammary tumorigenesis is that it occurs via a series of histologically recognizable intermediates that begin with normal tissue and progress through stages of hyperplasia, atypical hyperplasia, and carcinoma in situ, to invasive carcinoma and metastasis. Although this process has been intensively studies for decades, the molecular and cellular alterations that underlie this progression are poorly understood. As such, elucidating the molecular changes that are involved in tumor progression is a critical priority in breast cancer research. We have recently created a novel doxycycline-dependent bitransgenic mouse model system that permits oncogenes to be inducibly expressed in the mammary epithelium for a defined period of time, at a desired level, and during any desired developmental stage. Inducible expression of the c-MYC proto-oncogene using this system, for example, results in the formation of invasive mammary adenocarcinomas in a manner that is rapid, highly penetrant, mammary-specific, and absolutely dependent on transgene induction by doxycycline. The availability of rapid analytical tools that permit the parallel quantitative analysis of gene expression on a genome-wide scale, coupled with the ability to inducibly activate oncogenic pathways of known relevance to human breast cancer, makes it possible for the first time to provide a comprehensive description of the process by which mammary carcinogenesis occurs. A detailed analysis of the molecular changes that occur during successive stages of carcinogenesis will undoubtedly increase our understanding of the biological basis of breast cancer, lead to the ready identification of molecular differences between normal, precancerous, and cancerous cells, facilitate cancer detection and diagnosis, and ultimately identify potential new targets for therapeutic and preventative agents. This application is intended to demonstrate the suitability of oligonucleotide microarray technology for investigating mammary carcinogenesis by applying this technology to the analysis of a novel set of conditional bitransgenic model systems for breast cancer. The application consists of a first phase for technology evaluation, including proof -of -principle experiments demonstrating the accuracy, reproducibility and utility of the technology, and validating the transgenic animal models. In the second phase of this application, these novel animal models will be used in combination with high density oligonucleotide microarrays and novel analytical algorithms to define gene expression changes that occur during each of the stages of mammary carcinogenesis as induced by well- defined oncogenic stimuli relevant to human breast cancer.
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