Reproductive factors and family history of breast cancer are the most important predictors of an individual’s risk of developing breast cancer. These observations emphasize the important contributions of both genetic background and hormonal exposures in determining the risk of breast cancer. Mutations in tumor suppressor genes (TP53, BRCA1, BRCA2) render the breast epithelium at increased risk of forming tumors. These genes have pivotal roles in sensing DNA damage and ensuring appropriate cellular responses. Hormones that stimulate proliferation and direct breast development have also been shown to increase risk of breast cancer. However, hormonal exposures accompanying a single full-term pregnancy diminishes lifetime risk of breast cancer by half. It is the goal of our laboratory to define the molecular pathways that mediate susceptibility and resistance to breast cancer and design targeted therapeutics to prevent breast cancer.
Our laboratory has demonstrated an association between activity of the p53 tumor suppressor protein and incidence of mammary tumors. Expression and activity of p53 protein is responsive to hormonal stimuli and varies across different stages of mammary gland development. Therefore, a major focus of the laboratory is to discover the normal cellular mechanisms that regulate p53 expression and function and determine whether sustained elevation in p53 activity may prevent mammary tumors. Genetically engineered mice bearing targeted disruption of tumor suppressor genes and conditional overexpression of oncogenes are being used to identify factors that regulate p53 function. Genetic mapping strategies are also being used to identify low-penetrance modifiers of mammary tumor susceptibility that differ between strains of mice. Genes that regulate p53 function would provide novel targets for prevention and treatment of breast cancer. Through the use of contemporary techniques in molecular and cellular biology with animal models, we are defining the developmental biology of the breast epithelium itself, while providing both a genetic and cellular basis for susceptibility to breast cancer.
The mechanisms by which tumor suppressor genes regulate cancer susceptibility are important to numerous cellular processes. These genes arbitrate decisions of whether cells live or die in response to stress stimuli. They also interact with basic cellular machinery that ensures integrity of genomic DNA. These activities can be modulated to improve the efficiency of genetic modification in somatic cells. These approaches together with nuclear transplantation will make it possible to create genetically engineered animals to produce biomedical compounds and cell-based therapeutics.