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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035641-02
Application #
3173240
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1983-08-01
Project End
1987-01-31
Budget Start
1985-02-01
Budget End
1986-01-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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Hahm, H A; Ip, M M (1990) Primary culture of normal rat mammary epithelial cells within a basement membrane matrix. I. Regulation of proliferation by hormones and growth factors. In Vitro Cell Dev Biol 26:791-802
Hahm, H A; Ip, M M; Darcy, K et al. (1990) Primary culture of normal rat mammary epithelial cells within a basement membrane matrix. II. Functional differentiation under serum-free conditions. In Vitro Cell Dev Biol 26:803-14
Carter, C A; Ip, M M; Ip, C (1989) A comparison of the effects of the prostaglandin synthesis inhibitors indomethacin and carprofen on 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis in rats fed different amounts of essential fatty acid. Carcinogenesis 10:1369-74
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Leung, K H; Ip, M M (1986) Effect of dietary polyunsaturated fat and 7,12-dimethylbenz(a)-anthracene on rat splenic natural killer cells and prostaglandin E synthesis. Cancer Immunol Immunother 21:161-3
Leung, K H; Ip, M M; Koren, H S (1986) Regulation of human natural killing. IV. Role of lipoxygenase in regulation of natural killing activity. Scand J Immunol 24:371-80
Leung, K H; Ip, M M (1985) Regulation of rat natural killing. I. Inhibition of cytolysis and activation by protein synthesis inhibitors. Int J Immunopharmacol 7:857-63