The objective of this proposal is to study the mechanism of the dietary fat induced promotion of mammary carcinogenesis, with special emphasis being placed on the role of prostaglandins and of certain components of the host defense system in this process. An additional aim is to gain a greater understanding of the role of the prostaglandins in the regulation of immune surveillance during tumorigenesis, tumor growth, and metastatic spread. The specific experiments that will be done are as follows. (1) The role of the prostaglandins in the stimulation of DMBA-induced mammary tumorigenesis by diets high in polyunsaturated fat will be studied by using inhibitors at several steps of prostaglandin synthesis. This will include the use of drugs which block the cyclooxygenase, lipoxygenase, thromboxane synthetase and prostacyclin synthetase pathways. (2) The role of prostaglandins in the growth and metastatic spread of certain transplantable metastasizing mammary tumors will be examined in W/Fu rats. In these studies, manipulation of dietary fat intake in conjunction with specific prostaglandin synthesis inhibitors will be used to probe the role of prostaglandin synthesis inhibitors in cancer therapy. (3) Natural killer (NK) cell activity and macrophage function will be studied in rats fed different levels and types of fat to determine their role in DMBA-induced mammary tumorigenesis and in mammary tumor metatasis. Previous studies have demonstrated that NK activity is suppressed by prostaglandins and our goal is to determine whether agents that alter NK and macrophage activities can affect the growth and development of mammary tumors. (4) The effect of dietary fat on the cell-mediated immune response will be studied in SD rats with the goal of determining whether prostaglandin synthesis inhibitors or other agents can overcome the immune suppression caused by a high intake of polyunsaturated fat. The overall goal of these studies is to develop more effective therapeutic and/or immunoprophylactic treatment strategies for breast cancer, possibly utilizing specific prostaglandin synthesis inhibitors.
