The Impact of Fish Oil on the Chemopreventive Efficacy of Tamoxifen against Development ofN-Methyl-N-Nitrosourea–Induced Rat Mammary Carcinogenesis

Abstract

The antiestrogen tamoxifen reduces breast cancer incidence in high-risk women but is unable to inhibit the development of hormone-independent tumors. Omega-3 polyunsaturated fatty acids (n-3 PUFA), known ligands of the peroxisome proliferator activated receptor-γ (PPARγ), generally exert tumorsuppressive effects. Based on the known crosstalk between the estrogen and the PPARγ receptors, we tested the hypothesis that the combination of tamoxifen with n-3 PUFA results in a superior antitumor action over the individual interventions. In this study, we report for the first time that the combination of a fish oil diet rich in n-3 PUFA and tamoxifen seemed to inhibit N-methyl-N-nitrosourea-induced mammary carcinogenesis, tumor multiplicity, and volume to a greater extent than the individual interventions. The potential superiority of the combination was particularly evident at a suboptimal dose of tamoxifen, which, by itself, was unable to significantly decrease tumor development. Because activation of PPARγ is known to inhibit oxidative stress, we examined the effects of our interventions on circulating and tumor levels of glutathione, a major intracellular antioxidant. Our results indicate that reduction in the level of oxidative stress may be a potential mechanism by which the n-3 PUFA-rich diet potentiated the tumor-suppressive effect of tamoxifen. Our interventions were well tolerated without evidence of toxicity. Combined administration of tamoxifen and n-3 PUFA is a promising new approach to breast cancer prevention. Because of its safety, this combination can quickly be translated to the clinic if its superiority can be supported by future studies. Cancer Prev Res; 3(3); 322-30. ©2010 AACR.

Mammary Gland Density Predicts the Cancer Inhibitory Activity of the N-3 to N-6 Ratio of Dietary Fat

“…diet), mammary cancer incidence, cancer multiplicity, and cancer burden per rat were significantly reduced. Tamoxifen is known to cause a modest decrease in rate of body weight gain (36), and this was observed; however, the n-3: n-6 ratio had no effect on grow rate.…”

Chemical–Physical Changes in Cell Membrane Microdomains of Breast Cancer Cells After Omega-3 PUFA Incorporation

“…The set point is manually adjusted and kept as low as possible to obtain the best resolution while the total force applied on the sample during the imaging is approximately 300 pN as measured by force-distance curve. The 512x512 pixel 2 images are recorded at typical scan frequencies of 4-6 Hz. AFM images are flattened using the SPMLab NT Ver.…”

“…The main dietary sources of eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) are cold-water fish oils. Epidemiological studies have suggested that an increased n-3 PUFA intake might be associated with a reduced breast cancer incidence in humans [1][2][3]. A number of mechanisms have been proposed for the anticancer actions of n-3 PUFA, including suppression of neoplastic transformation, inhibition of cell proliferation, enhancement of apoptosis, and antiangiogenic action.…”

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

“…In addition, within the polyunsaturated fatty acids the ratio of n-3: n-6 fatty acids was varied from 25:1 to 1:25 to provide a robust evaluation of the role of this ratio in affecting the postinitiation phase of 1-methyl-1-nitrosourea (MNU)-induced mammary carcinogenesis in the rat (4). Our laboratories were the first to show that the combination of n-3 fatty acids with Tamoxifen was a more effective chemopreventive regimen than the individual interventions (4,9). Specifically, we observed that high n-3:n-6 ratios (10:1 and 25:1) were able to suppress carcinogenesis in Tamoxifentreated animals, thus suggesting that they are able to inhibit the development of hormone-resistant tumors.…”