The long term objective of this project is to determine how dietary fatty acids influence the progression of breast cancer. A secondary objective is to develop combinations of dietary interventions and pharmacological agents which suppress this progression in an appropriate animal model. The short term goals are: first, to explore further interrelations between dietary fatty acids, lipoxygenase products, and proteolytic enzyme expression in the invasive process; second, to extend these studies to include lipoxygenase product-mediated activation of protein kinase (PKC); third, to determine whether the poor invasive and metastatic capability of estrogen receptor positive breast cancer cell lines is related to a low level of 12-lipoxygenase (12-LOH) activity and impaired 12-hydroxyeicosa-tetraenoic acid (12-HETE) synthesis. The first specific aim will determine the effects of n-6 and n-3 fatty acids on the metastatic potential of MDA-MB-231 and MDA-MB-435 estrogen-independent human breast cancer cells in nude mice. The second specific aim is to test the hypothesis that estrogen independent breast cancer cells progress to a more highly metastatic phenotype that is associated with enhanced expression of vimentin and proteolytic activity as a consequence of an induction of 12-LOX activity through 12-HETE-mediated PKC activation. The applicant proposes to evaluate this hypothesis both in vitro and in vivo. In the proposed in vitro studies, breast cancer cell lines with different degrees of estrogen dependence and independence will be examined and compared for invasive activity, vimentin and protease expression, and PKC activity for the effects of the n-6 amino acids (LA and AA), also, 12-HETE will be assessed on the expression of these compounds of the metastatic phenotype. In addition, the same cell lines will be grown in the mammary fatpad of nude mice and the capacity for spontaneous metastases compared in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA053124-07
Application #
2894860
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1992-08-01
Project End
2000-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Institute for Cancer Prevention
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Rose, D P; Connolly, J M (2000) Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids. Nutr Cancer 37:119-27
Connolly, J M; Gilhooly, E M; Rose, D P (1999) Effects of reduced dietary linoleic acid intake, alone or combined with an algal source of docosahexaenoic acid, on MDA-MB-231 breast cancer cell growth and apoptosis in nude mice. Nutr Cancer 35:44-9
Rose, D P; Connolly, J M (1999) Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther 83:217-44
Rose, D P; Connolly, J M (1999) Antiangiogenicity of docosahexaenoic acid and its role in the suppression of breast cancer cell growth in nude mice. Int J Oncol 15:1011-5
Morse-Gaudio, M; Connolly, J M; Rose, D P (1998) Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype. Int J Oncol 12:1349-54
Connolly, J M; Rose, D P (1998) Enhanced angiogenesis and growth of 12-lipoxygenase gene-transfected MCF-7 human breast cancer cells in athymic nude mice. Cancer Lett 132:107-12
Rose, D P; Connolly, J M; Liu, X H (1997) Fatty acid regulation of breast cancer cell growth and invasion. Adv Exp Med Biol 422:47-55
Rose, D P (1997) Dietary fatty acids and prevention of hormone-responsive cancer. Proc Soc Exp Biol Med 216:224-33
Rose, D P (1997) Effects of dietary fatty acids on breast and prostate cancers: evidence from in vitro experiments and animal studies. Am J Clin Nutr 66:1513S-1522S
Rose, D P (1997) Dietary fatty acids and cancer. Am J Clin Nutr 66:998S-1003S

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