The long term objective of this proposal is to study the role of cyclooxygenase prducts of arachidonic acid metabolism in tumor growth and metastasis. For these studies, a murine model of mammary adenocarcinoma will be used. Despite intensive study, the factors that control the growth of breast cancer cells are poorly understood. Prostaglandins, the major products of cyclooxygenase metabolism, are synthesized in abnormally high levels by breast cancer cells and contribute to the progressive growth of these lesions. Clinically, the most difficult problem in the management of breast cancer is the occurrence of metastasis and, again, prostaglandins contribute to this poorly understood process.
The specific aims of this proposal are (1) to elucidate the mechanisms by which cyclooxygenase products interact with immune effector cells in the control of primary tumor growth, (2) to identify the mechanisms by which cyclooxygenase products interact with immune effector cells in the control of tumor metastasis and (3) to expand the characterization of prostaglandin binding to mammary tumor cells and normal mammary epithelium and to determine the functional significance of the heterogeneity of binding to different tumor lines. These studies will be carried out using a series of murine mammary tumor cell lines that were originally derived from one spontaneously occurring mammary tumor. These closely related lines differ in many properties including tumorigenicity, immunogenicity, metastatic potential and prostaglandin synthetic activity. We will manipulate the immunologic system and prostaglandin metabolism to define the role of each factor and to describe the interactions that affect tumor growth and metastasis. This proposal requires both in vivo and in vitro studies of immune effector function. Studies of prostaglandin binding in vitro require cultured mammary tumor cells.
