P53 Gene Mutagenesis in Breast Cancer

摘要

The incidence and mortality from breast cancer varies significantly in ethnically and geographically distinct populations from the United States, Western Europe and Japan. The central hypothesis of this proposal is that variability in the patterns of p53 mutagensis in breast cancer reflects differences in exposures to different amounts and/or types of diverse environmental mutagens. We postulate that mammary cells are exquisitely sensitive to lipophilic mutagens in the diet because of the unique architecture of breast tissue, i.e., tiny islands of cancer-prone rapidly dividing mammary cells surrounded by a sea of fat cells. It has now become possible to measure mutation load in an individual by identifying p53 mutations in the normal mammary cells in an individual. This new tool greatly increases the power to test the central hypothesis. we propose to test twenty upper Midwest U.S. women with breast cancer, ten with diets high in animal fat and ten with diets low in animal fat. In each woman, 30 different mutations will be defined in mammary cells. The normal breast tissue is obtained away from the tumor margin in women with breast cancer. With this newly developed technique, it is possible to determine the mutation fingerprint in each woman and correlate this with her diet type. it is hypothesized that there will be substantial individual variation in mutation patterns within the population consistent with a key prediction of the 'lipophilic mutagens hypothesis'.