The goal of this project is to identify potential targets for chemoprevention and biomarkers of chemopreventive efficacy shared between ER negative breast cancers and hormonally non-responsive mouse models of mammary carcinogenesis. Since the development of solid tumors is associated with the acquisition of genetic alterations and corresponding changes in gene expression that modify normal growth control and survival pathways, we will use genomic analyses, including array-based measurements of DNA copy number alterations and gene expression to identify alterations occurring at both the DNA and mRNA expression levels in ER negative tumors and mouse models.
In Aim 1, we will classify ER negative breast tumors according to copy number and expression phenotypes and further characterization of the tumors by determining the status of p53 mutations and telomerase activity.
In Aim 2, we will use the array CGH and expression profiles to identify regions of most recurrent aberration or altered gene expression characteristic of each subtype. These aberrations will be evaluated as candidate early lesions in surrounding histologically """"""""normal"""""""" or hyperplastic tissue and in cell culture systems.
In Aim 3, we will characterize mouse models of mammary tumorigenesis to determine which ones correspond most closely to the human tumor classes identified in Aims 1 and 2. We will then determine if the early markers that were useful in the human are also informative in the corresponding mouse models. The successful conclusion of these studies will define the features of ER negative breast tumors and will lead to the characterization of recurrent abnormalities suitable for use as surrogate biomarkers. In addition, these studies will determine which mouse models most closely resemble different subtypes of ER negative tumors at the molecular level, thereby enhancing their utility as preclinical models.
