Human population studies and experimental animal models indicate that fatty acid saturation may be a key factor in determining whether a particular fat promotes or inhibits the development of breast cancer. The proposed studies address mechanisms at the cellular level that may account for the reported divergent effects of different fatty acids. The major focus is on cell surface proteoglycans (PGly) as important mediators of tumorigenic potential. The overall hypothesis is that PGly metabolism represents a level of regulation of the tumorigenic potential of mammary cells that is modified by dietary fatty acids. Specific hypotheses are .that n-3 polyunsaturated fatty acids (PUFA) enhance the expression of the PGly, syndecan 1 and that this regulation is mediated by the peroxisome proliferators receptor (PPAR) gamma transcriptional pathway. The resulting increase in syndecan 1 inhibits the tumorigenic potential of the cells by decreasing growth and increasing apoptosis. A unique feature of the studies is the use of low density lipoproteins (LDL) and the LDL receptor pathway to deliver fatty acids to the cells. Since LDL receptors are upregulated in tumor cells, this pathway is likely to represent a major route for delivery of fatty acids in vivo. Studies will use LDL obtained from African green monkeys fed dietary fats proposed to have opposite effects in human breast cancer: n-6 PUFA (tumor promoting) and n-3 PUFA (tumor inhibiting).
Four Specific Aims are proposed.
In Aim 1, studies will examine metabolism of the LDL by non-tumorigenic mammary cells and breast cancer cell lines and compare delivery of PUFA to cell membranes by LDL and non LDL-receptor dependent pathways.
In Aim 2, the emphasis will be effects of LDL-delivered PUFA on the cell surface PGly, syndecan 1. Using biochemical, molecular biologic and immunologic techniques, studies will examine effects of LDL on syndecan synthesis, structure and gene regulation in non-tumorigenic and tumorigenic breast cells. In addition, using a transgenic mouse model engineered to produce n-3 PUFA; studies will examine syndecan 1 expression in an enhanced in vivo n-3 PUFA environment.
In Aim 3, studies will investigate the involvement of the PPARy transcriptional pathway in the n-3 PUFA regulation of syndecan 1.
In Aim 4, using syndecan 1-transfected cells we will test the hypothesis that increased production of syndecan 1 has a significant effect on cell growth and apoptosis. Data will provide important new information on mechanisms by which intake of specific dietary fats may affect the metabolism and behavior of both non-tumorigenic and tumorigenic human breast cells and provide rationale for dietary modifications aimed at breast cancer risk reduction or survival.
|O'Flaherty, Joseph T; Wooten, Rhonda E; Samuel, Michael P et al. (2013) Fatty acid metabolites in rapidly proliferating breast cancer. PLoS One 8:e63076|
|Hu, Yunping; Sun, Haiguo; O'Flaherty, Joseph T et al. (2013) 15-Lipoxygenase-1-mediated metabolism of docosahexaenoic acid is required for syndecan-1 signaling and apoptosis in prostate cancer cells. Carcinogenesis 34:176-82|
|O'Flaherty, Joseph T; Hu, Yungping; Wooten, Rhonda E et al. (2012) 15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival. PLoS One 7:e45480|
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|Sun, Haiguo; Hu, Yunping; Gu, Zhennan et al. (2011) Endogenous synthesis of n-3 polyunsaturated fatty acids in Fat-1 mice is associated with increased mammary gland and liver syndecan-1. PLoS One 6:e20502|
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|Hu, Yunping; Sun, Haiguo; Owens, Rick T et al. (2009) Decorin suppresses prostate tumor growth through inhibition of epidermal growth factor and androgen receptor pathways. Neoplasia 11:1042-53|
|Sun, Haiguo; Berquin, Isabelle M; Owens, Rick T et al. (2008) Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells. Cancer Res 68:2912-9|
|Edwards, Iris J; Sun, Haiguo; Hu, Yunping et al. (2008) In vivo and in vitro regulation of syndecan 1 in prostate cells by n-3 polyunsaturated fatty acids. J Biol Chem 283:18441-9|
|Berquin, Isabelle M; Edwards, Iris J; Chen, Yong Q (2008) Multi-targeted therapy of cancer by omega-3 fatty acids. Cancer Lett 269:363-77|
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