Abstract 5722: Effects of dietary omega-3 and omega-6 in the prevention of rat mammary cancer with tamoxifen
Authors: Vanegas Johana E. , Bidinotto Lucas T. , Pereira Julia S. , Lopez Ricardo , Washington Sharlene , Xu Haifang , Aliaga Cesar , Russo Irma H. , Manni Andrea , El-Bayoumy Karam , Russo Jose 
Published: February 2011

Abstract
There is evidence that omega 3-rich diet strengthened the inhibitory effect of tamoxifen on the development of estrogen dependent tumors, pointing to omega 3 as a potential adjuvant to standard therapy (Manni A. et al. Cancer Prev Res, in press). However, the mechanistic basis of this observation is unknown. The objective of the present work is to analyze the genomic changes in chemically induced mammary tumors that developed in tamoxifen treated rats fed omega 3 or omega 6 fatty acids. Sprague Dawley rats, 21 days-old, were administered an i.p. injection of 1-Methyl-1-nitrosourea (MNU) 50 mg/kg body weight. The animals were distributed into 4 groups (G), and maintained under standard conditions and were given the following treatments for 8 weeks: G1 received a diet of 20% of corn oil (CO); G2 received a diet with 17% of fish oil (FO) and 3% CO; G3 received the CO diet and tamoxifen; G4 received FO diet and tamoxifen. Tamoxifen was administered s.c 100 μg/Kg b.w., 5 days/week. The animals were euthanized after 8 weeks. Mammary tumors were frozen in liquid nitrogen and stored at −80C. RNA from cribiform tumors was extracted and one-color Agilent 44K whole rat genome oligonucleotide microarray was performed in three tumor samples per group. Tamoxifen-treated groups (G3 and G4) were compared with their respective controls (G1 and G2). The genes were considered differentially expressed when the p value was lower or equal to 0.01 and had at least 1.50 fold change. A total of 488 genes were considered statistically different comparing G3 to G1 (G3/G1), whereas 206 genes were considered statistically different comparing G4 to G2 (G4/G2). Gene ontology analysis showed that 125 genes of G3/G1 comparison and 58 of G4/G2 comparison were related to cancer, apoptosis, cellular movement, cellular proliferation, inflammatory response or angiogenesis. In the G3 /G1 comparison, the expression pattern of genes related to cell proliferation and apoptosis was found to be divergent, as well as the genes related to cell proliferation in the G4/G2 comparison. In contrast, G4/G2 did not showed relevant genes expressed related to apoptosis.
CO treatment in presence of tamoxifen (G3/G1) induced an up-regulation of C5r1, Hck, Il6Ra, Myo1f_predicted and Tlr6, and down-regulation of Mif, indicating an increase of the inflammatory host response. These changes were accompanied by up-regulation of Ets1, Tlr6 and Wdr44 genes controlling angiogenesis and cell migration, which can lead to metastasis. These changes were not observed in the FO and tamoxifen treated group. We conclude that an omega 6 rich-diet could modify the genomic profile of tamoxifen treated tumors making them more prone to an aggressive behavior or result in tamoxifen resistance. (Supported by the Susan G. Komen for the Cure, grant KG081632). The first two authors contributed equally to this work.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5722.