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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037943-06
Application #
3175900
Study Section
Experimental Immunology Study Section (EI)
Project Start
1989-02-01
Project End
1992-01-31
Budget Start
1990-02-01
Budget End
1992-01-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Zhang, S Z; Fulton, A M (1994) Modulation of integrin-laminin receptor function on mammary tumor cells by prostaglandin E2 receptor antagonism. Cancer Lett 85:233-8
Fulton, A M; Chong, Y C (1992) Prostaglandin E2 receptor activity and susceptibility to natural killer cells. J Leukoc Biol 51:176-80
Fulton, A M; Zhang, S Z; Chong, Y C (1991) Role of the prostaglandin E2 receptor in mammary tumor metastasis. Cancer Res 51:2047-50
Zhang, S Z; Fulton, A M (1991) Prostaglandin E2 receptor modulation affects tumor cell adhesion to laminin. J Cell Physiol 149:208-13
Wei, W Z; Fulton, A; Winkelhake, J et al. (1989) Correlation of natural killer activity with tumorigenesis of a preneoplastic mouse mammary lesion. Cancer Res 49:2709-15
Fulton, A M; Laterra, J J; Hanchin, C M (1989) Prostaglandin E2 receptor heterogeneity and dysfunction in mammary tumor cells. J Cell Physiol 139:93-9
Chong, Y C; Heppner, G H; Paul, L A et al. (1989) Macrophage-mediated induction of DNA strand breaks in target tumor cells. Cancer Res 49:6652-7
Fulton, A M (1988) Inhibition of experimental metastasis with indomethacin: role of macrophages and natural killer cells. Prostaglandins 35:413-25
Fulton, A M (1988) The role of eicosanoids in tumor metastasis. Prostaglandins Leukot Essent Fatty Acids 34:229-37
Fulton, A M (1987) Interactions of natural effector cells and prostaglandins in the control of metastasis. J Natl Cancer Inst 78:735-41