Effect of ω-3 and ω-9 fatty acid rich oils on lipoxygenases and cyclooxygenases enzymes and on the growth of a mammary adenocarcinoma model (original) (raw)
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Implications of dietary ω-3 and ω-6 polyunsaturated fatty acids in breast cancer
Experimental and therapeutic medicine, 2018
Breast cancer represents one of the most common forms of cancer in women worldwide, with an increase in the number of newly diagnosed patients in the last decade. The role of fatty acids, particularly of a diet rich in ω-3 and ω-6 polyunsaturated fatty acids (PUFAs), in breast cancer development is not fully understood and remains controversial due to their complex mechanism of action. However, a large number of animal models and cell culture studies have demonstrated that high levels of ω-3 PUFAs have an inhibitory role in the development and progression of breast cancer, compared to ω-6 PUFAs. The present review focused on recent studies regarding the correlation between dietary PUFAs and breast cancer development, and aimed to emphasize the main molecular mechanisms involved in the modification of cell membrane structure and function, modulation of signal transduction pathways, gene expression regulation, and antiangiogenic and antimetastatic effects. Furthermore, the anticancer ...
Clinical & Experimental Metastasis
Epidemiological studies show a reduced risk of breast cancer (BC) in women consuming high levels of long-chain (LC) omega-3 (ω-3) fatty acids (FAs) compared with women who consumed low levels. However, the regulatory and mechanistic roles of dietary ω-6 and LC-ω-3 FAs on tumor progression, metastasis and survival are poorly understood. Female BALB/c mice (10-week old) were pair-fed with a diet containing ω-3 or an isocaloric, isolipidic ω-6 diet for 16 weeks prior to the orthotopic implantation of 4T1 mammary tumor cells. Major outcomes studied included: mammary tumor growth, survival analysis, and metastases analyses in multiple organs including pulmonary, hepatic, bone, cardiac, renal, ovarian, and contralateral MG (CMG). The dietary regulation of the tumor microenvironment was evaluated in mice autopsied on day-35 post tumor injection. In mice fed the ω-3 containing diet, there was a significant delay in tumor initiation and prolonged survival relative to the ω-6 diet-fed group. The tumor size on day 35 post tumor injection in the ω-3 group was 50% smaller and the frequencies of pulmonary and bone metastases were significantly lower relative to the ω-6 group. Similarly, the incidence/ frequencies and/or size of cardiac, renal, ovarian metastases were significantly lower in mice fed the ω-3 diet. The analyses of the tumor microenvironment showed that tumors in the ω-3 group had significantly lower numbers of proliferating tumor cells (Ki67 +)/high power field (HPF), and higher numbers of apoptotic tumor cells (TUNEL +)/HPF, lower neo-vascularization (CD31 + vessels/HPF), infiltration by neutrophil elastase + cells, and macrophages (F4/80 +) relative to the tumors from the ω-6 group. Further, in tumors from the ω-3 diet-fed mice, T-cell infiltration was 102% higher resulting in a neutrophil to T-lymphocyte ratio (NLR) that was 76% lower (p < 0.05). Direct correlations were observed between NLR with tumor size and T-cell infiltration with the number of apoptotic tumor cells. qRT-PCR analysis revealed that tumor IL10 mRNA levels were significantly higher (six-fold) in the tumors from mice fed the ω-3 diet and inversely correlated with the tumor size. Our data suggest that dietary LC-ω-3FAs modulates the mammary tumor microenvironment slowing tumor growth, and reducing metastases to both common and less preferential organs resulting in prolonged survival. The surrogate analyses undertaken support a mechanism of action by dietary LC-ω-3FAs that includes, but is not limited to decreased infiltration by myeloid cells (neutrophils and macrophages), an increase in CD3 + lymphocyte infiltration and IL10 associated anti-inflammatory activity.
Cancer Letters, 1998
It is widely known that dietary lipids can modify the ability of different cancers to grow up and metastasize, especially mammary gland tumors. However, it is still unclear whether n-6 fatty acids behave as tumor promoters in this gland cell population. The effect of different nutritional polyunsaturated fatty acids (PUFAs) on tumor growth parameters of two transplantable murine mammary gland adenocarcinomas of low and high metastatic ability was tested on hosts fed diets with corn oil (CO) rich in 18:2n-6, evening primrose oil (EPO) containing 18:3n-6 (GLA) and a third formula supplemented with olein (O) 18:1n-9, which induces an essential fatty acid deficiency (EFAD). Tumor growth parameters were not adversely affected in the corn oil group with respect to stock-fed controls. Furthermore, metastatic spreading diminished in this group. EPO showed a moderate antitumor activity whereas the n-9-enriched diet showed no clear-cut effects. In both mammary gland tumors, n-6 fatty acid-rich lipids formulae, containing GLA and linoleic acid, were not tumor promoters. On the contrary, both exhibited anticancer activity.
Nutrients
In order to understand how omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplements affect breast cancer prevention and treatment, a systematic review of articles published in the last 5 years in two databases was performed. Of the 679 articles identified, only 27 were included and examined based on five topics, taking into account: the induction type of the breast cancer used in animal models; the characteristics of the induction model by cell transplantation; the experimental design of the ω-3 supplementation—combined or not with a treatment antitumor drug; the fatty acids (FAs) composition used; the analysis of the studies’ outcomes. There are diverse and well-established animal models of breast cancer in the literature, with very relevant histological and molecular similarities depending on the specific objective of the study, such as whether the method of tumor induction was transgenic, by cell transplantation, or by oncogenic drugs. The analyses of outcomes were mainly focuse...
Carcinogenesis, 1998
Dietary n-6 polyunsaturated fatty acids (PUFAs) promote rat mammary cancer while n-3 PUFAs are inhibitory. The purpose of this study was to determine whether the fats exert their effects by altering the expression of genes that affect cancer development. Therefore, we have examined the effect of PUFAs on the expression of the cyclooxygenase (COX) 1 and 2 genes that are involved in prostaglandin biosynthesis. We also investigated the effect of dietary PUFAs on the expression of the p21 ras protein and Ha-ras mRNA. Rats were fed either low-(7%; LF) or high-(21%; HF) fat diets that were rich in either n-6 PUFAs (safflower oil, S) or n-3 PUFAs (menhaden oil, M) for 3 weeks. COX-1 mRNA levels were approximately the same in groups fed diets containing either level of menhaden oil, but were increased by~30% in the LFS and HFS groups (P Ͻ 0.05). Transcripts of the inducible COX-2 gene were not detectable in the menhaden oil groups, but this gene was expressed in animals fed either level of safflower oil and in the HFS group was associated with increased levels of COX enzymatic activity and production of PGE 2 . Animals fed safflower oil had elevated levels of p21 ras protein compared to animals fed menhaden oil. Ha-ras mRNA was increased by~35% in animals fed HFS compared to the group fed HFM (P < 0.05). These results demonstrate that dietary n-6 PUFAs upregulate COX-2 and, to some extent, COX-1 expression. There was a concomitant increase in COX enzyme activity and PG synthesis in the mammary glands of rats fed high levels of n-6 PUFAs. Together with associated changes in p21 ras expression, these results may explain, at least in part, the promoting effects of dietary n-6 PUFAs on mammary carcinogenesis. *Abbreviations: PUFAs, polyunsaturated fatty acids; PG, prostaglandin; NSAIDs, non-steroidal anti-inflammatory drugs; LA, linoleic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; COX, cyclooxygenase; AA, arachidonic acid; LFM, low fat menhaden; HFM, high fat menhaden; HFS, high fat safflower; LFS, low fat safflower.
Breast Cancer Research and Treatment, 2004
Effects of a high corn oil and a high olive oil diet on the histopathologic characteristics of rat dimethylbenz(α)anthracene-induced mammary adenocarcinomas were investigated in comparison with those of a control low-fat diet. Two experimental series (A and B) studied the influence of a high corn oil diet on the initiation and the promotion of mammary carcinogenesis, while another one (C) assessed the effects of the two dietary lipids on the promotion. Nine parameters have been analyzed and a new histologic grading method, adapted to rat tumors, has been applied in each carcinoma. High corn oil diets, particularly when acting as promoters, associated with higher-grade carcinomas than control (p p
Clinical & Translational Oncology, 2002
The dietary fat hypothesis postulates that dietary or exogenously derived fatty acids play an important role in the carcinogenesis, evolution and/or progression of breast cancer. In order to reveal possible underlying mechanisms of this hypothesis, we studied the influence of ω- 3 polyunsaturated fatty acids (PUFAs) -α-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA)-, ω-6 PUFAs-linoleic (LA), γ-linolenic (GLA) and arachidonic (ARA)- and monounsaturated ω- 9 oleic acid (OA) on the proliferation, adhesion and metastatic potential of human breast cancer cells in culture. GLA and the ω-3 PUFAs, ALA and DHA, inhibited significantly the cell growth of MCF-7 and MDA-MB-231 breast cancer cell lines, while EPA has less marked inhibitory effects. ω-6 PUFAs, LA and ARA, or ω- 9 OA had either no effect or caused a slight increase of proliferation. The attachment of breast cancer cells to the extracellular matrix components (type IV collagen, fibronectin and Matrigel) was significantly inhibited by ω-6 GLA and ω-3 PUFAs ALA, DHA and EPA. At concentrations which had no effect on cell growth over the duration of experiments the ω-6 PUFAs, LA and GLA, and the ω-3 PUFAs, ALA, DHA and EPA, had the ability to inhibit both cellular migration and invasion into type IV collagen and Matrigel. In summary, our findings indicate important differences in the ability of ω-3, ω-6 and ω-9 fatty acids to modulate prolif eration, attachment to extracellular matrix components, mo-tility and invasiveness of human breast carcinoma cells in vitro, with the GLA and all ω-3 PUFAs being the most effective inhibitors. Our data are consistent with the view that the type rather than the amount of dietary fatty acids is be more important in breast cancer development and progression. Los ácidos grasos exógenos o procedentes de la dieta podrían jugar un papel importante en la carcinogénesis, evolución y/o progresión del cáncer de mama. Para estudiar los posibles mecanismos que subyacen a esta hipótesis hemos estudiado en cultivo, la influencia de los ácidos grasos poliinsaturados (PUFAs) ω-3 -α-linolénico (ALA), eicosapentaenoico (EPA) y docosahexaenoico (DHA)-, los PUFAs ω-6 -linoleico (LA), γ-linolénico (GLA) y araquidónico (ARA)- y el ácido graso monoinsaturado ω-9 ácido oleico (OA) en la proliferación, adhesión y potencial metastásico de las células humanas de cáncer de mama. El GLA y los PUFAs ω-3 ALA y DHA inhibieron significativamente el crecimiento de las células de cáncer de mama, mientras que los efectos inhibidores del EPA fueron menos marcados. Los PUFAs ω-6, LA y ARA, o el ω-9 OA no modificaron o produjeron un débil incremento de la proliferación. La adhesión de las células de cáncer de mama a componentes de la matriz extracelular (colágeno tipo IV, fibronectina y Matrigel) fue inhibida significativamente por el ω-6 GLA y por los PUFAs ω-3 ALA, DHA y EPA. A las concentraciones que no afectó el crecimiento celular durante el transcurso de los experimentos, los PUFAs ω-6 LA y GLA y los PUFAs ω-3 ALA, DHA y EPA inhibieron la migración e invasión celulares en el colágeno tipo IV y el Matrigel. En resumen, nuestros resultados indican que existen diferencias importantes en la capacidad de los ácidos grasos ω-3, ω-6 y ω-9 para modular in vitro la proliferación, adhesión a componentes de la matriz extracelular, motilidad e invasividad de las células humanas de cáncer de ma-ma, siendo el GLA y los PUFAs ω-3 los inhibidores más efectivos. Los resultados son consistentes con la opinión de que, más que la cantidad total, es el tipo de ácido graso en la dieta el factor más importante en el desarrollo y progresión del cáncer de mama.
Cancer research, 1997
United States diet that contains high levels of omega-6 PUFAs,' such as linoleic acid (cl8:2, n-6), enhances colon tumorigenesis in rodents, whereas fish oil, which is rich in omega-3 PUFAs, such as EPA (c20:5, n-3) and DHA (c22:6, n-3), reduces colon carcinogenesis. Evidence also indicates that consumption of dietary fish oil is asso ciated with suppressed inflammatory response in patients with rheu matoid arthritis (1 1) and psoriasis (12), reduced mortality from cancer and cardiovascular disease (6, 13, 14), and improved survival of animals with endotoxin challenge or burn injury (15). However, the precise mechanism by which fish oil and other omega-3 PUFAs exert their anti-inflammatory, antitumor, antithrombogenic, and immuno modulating effects remains largely unknown. Accumulating evidence from epidemiological and laboratory ani mal studies indicates that chronic ingestion of NSAIDs, such as aspirin, piroxicam, and sulindac, is associated with a reduced risk of death from colon cancer (16), decreased incidence of colon cancer (17â€"19),reduction in number and size of colonic polyps and adeno mas in human familial adenomatous polyposis (20, 21), and protection against chemically induced colon cancer in animal models (22). Although the molecular mechanism by which NSAIDs inhibit cob rectal carcinogenesis remains unknown, it is likely that it involves inhibition of prostaglandin-endoperoxide synthase enzyme, also called COX, which in a rate-limiting step catalyzes the conversion of arachidonic acid into prostaglandins that are potent biological medi ators of diverse normal physiological effects and are implicated in various pathological conditions including inflammation and neoplas tic transformation (23, 24). An inducible isoform of COX, designated COX-2, has been characterized as an immediate early response gene, which, bikec-fos and c-fun, is rapidly induced following stimulation of quiescent cells by mitogenic and hormonal stimuli (25). Overexpres sion of COX-2 has been reported in about 90% of colon tumors and premalignant coborectal adenomas (26, 27) and also in histologically normal-appearing epithelium in Mm mice (28). Both COX-l and COX-2 are the targets of NSAIDs, and the treatment with NSAIDs is associated with a decrease in COX-2 in colon tumors (26). In a recent double-blind study from our laboratory (29), a specific COX-2 inhib itor was shown to effectively suppress the development of chemically induced aberrant crypt foci, a putative premalignant lesion. It is interesting that the omega-3 PUFAs EPA and DHA, which are present in fish oil, havebeenshownto inhibit COX activity and arachidonic acid metabolism (30). Moreover, when rats were fed omega-3 PUFAs, a selective incorporation of omega-3 PUFAs with concomitant reduc tion of omega-6 PUFAs in membrane phospholipid pool of cells in various tissues was shown to occur (3 1), which may affect the physiological properties of cell membrane and membrane-bound en zymes that regulate the sensitivity of cells to carcinogenic stimuli and tumor growth. It is hypothesized that the inhibition of colon carcino genesis by omega-3 PUFAs may be mediated through the suppression 3 The abbreviations used are: PUFA, polyunsaturated fatty acid; NSAID, nonsteroidal anti-inflammatory drug; HFCO, high-fat com oil; HFFO, high-fat fish oil; LFCO. low-fat com oil; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; COX. cycbooxygen ase; AOM, azoxymethane; AIN, American Institute of Nutrition; TBST, Tris-buffered saline containing 0.2% Tween 20.
The Journal of Nutritional Biochemistry, 2001
The aim of this study was to analyze the effects of a polyunsaturated n-6 high-fat diet on rat DMBA-induced breast cancer at different stages of the carcinogenesis and to investigate if changes in the tumor fatty acid composition are one of the mechanisms by which dietary lipids could exert their effects. 14 fatty acids were evaluated in 6 lipid fractions. The results firstly showed that this high-fat diet stimulated the malignant mammary tumor growth, mainly all in the promotion group. The tumor lipid analysis indicated: 1) that each lipid fraction presented distinct major fatty acids (Ͼ5%) which were not the most abundant in the diet, except in the case of the triacylglicerides, suggesting the different resistance to dietary fatty acid modification of the tumor lipid fractions; 2) a higher arachidonic acid content in the fractions with less linoleic acid, above all in phospholipids, particularly in the phosphatidylethanolamine, indicating a different efficiency of conversion; 3) the three most abundant fatty acids in the dietary lipid (18:2n-6, 18:1n-9 and 16:0) were those which essentially displayed the differences between groups; thus, the high-fat diet changed the tumor lipid profile, increasing the 18:2n-6 relative content and decreasing that of the 18:1n-9; differences were significant in phosphatidylcholine, free fatty acids and triacylglycerides. Any change was obtained in the phosphatidylinositol. The greatest number of differences was found in the promotion group. Taken as a whole, our results suggest the different roles of lipid fractions in breast cancer cells and an association between cancer malignancy and the content of linoleic and oleic acids.