Sauer LA, Dauchy RT, and Blask DE,Polyunsaturated fatty acids, melatonin, and cancer prevention. Biochem Pharmacol, 2001;61(12):1455-1462

Many nutritional, hormonal, and environmental factors affect carcinogenesis and growth of established tumors in rodents. In some cases, these factors may either enhance or attenuate the neoplastic process.

Recent experiments performed in our laboratory using tissue-isolated rat hepatoma 7288CTC in vivo or during perfusion in situ have demonstrated new interactions among four of these factors. Two agents, dietary linoleic acid (C18:2n6) and "light at night," enhanced tumor growth, and two others, melatonin and n3 fatty acids, attenuated growth. Linoleic acid stimulated tumor growth because it is converted by hepatoma 7288CTC to the mitogen, 13-hydroxyoctadecadienoic acid (13-HODE).

Melatonin, the neurohormone synthesized and secreted at night by the pineal gland, and dietary n3 fatty acids are potent antitumor agents. Both inhibited tumor linoleic acid uptake and 13-HODE formation. Artificial light, specifically "light at night," increased tumor growth because it suppressed melatonin synthesis and enhanced 13-HODE formation.

Melatonin and n3 fatty acids acted via similar or identical G(i) protein-coupled signal transduction pathways, except that melatonin receptors and putative n3 fatty acid receptors were used. The results link the four factors in a common mechanism and provide new insights into the roles of dietary n6 and n3 polyunsaturated fatty acid intake, "light at night," and melatonin in cancer prevention in humans.

Hilakivi-Clarke L, Cho E, Cabanes A, et al. Dietary Modulation of Pregnancy Estrogen Levels and Breast Cancer Risk among Female Rat Offspring. Clinical Cancer Research, 2002; 8; 3601-3610.

Purpose:
Against the hypothesis that high estrogen levels in utero increase the risk of developing breast cancer in later life are data showing that pregnancy estrogen levels are significantly higher in Asian women who have low breast cancer risk than in Caucasian women.

We investigated whether maternal dietary intake of genistein or n-3 polyunsaturated fatty acids (PUFAs), which are typical to Asian but not Caucasian diet, affect pregnancy estrogen levels and susceptibility to mammary tumorigenesis among offspring.

Experimental Design:
For that purpose, pregnant female Sprague Dawley rats were fed isocaloric AIN-93-based diets containing either at 15 mg (low), 150 mg (medium), or 300 mg (high)/kg genistein/diet or low- or high-fat (16 versus 39% energy from fat) diet composed either of n-3 PUFA menhaden fish oil or n-6 PUFA corn oil. All diets were switched to regular AIN-93 diet when pups were born.

Results:
Maternal intake of n-3 PUFA diets significantly increased pregnancy 17?estradiol (E2) levels (48% increase when compared with high n-6 PUFA diet; P < 0.0045).
High genistein exposure also increased pregnancy estrogen levels, but the increase did not reach statistical significance (P < 0.14).

The offspring of high-fat n-3 PUFA-consuming dams were significantly less likely to develop 7,12-dimethylbenz-[a]anthracene-induced mammary tumors (38% of these rats developed tumors during week 17 versus 64% of high n-6 PUFA offspring; P < 0.003).

Maternal genistein intake did not affect offsprings tumor incidence. The mammary glands of high fat n-3 PUFA offspring contained more lobules (P < 0.07) and were thus more differentiated, whereas the glands of high genistein offspring contained more terminal end buds (P < 0.0015), which are the sites of malignant transformation.

Conclusions:
Our findings indicate that the elevated estrogen levels in the n-3 PUFA mothers were linked to reduced rather than increased breast cancer risk among their offspring, suggesting that other effects of n-3 PUFA may counteract the effects of high fetal estrogenicity on the mammary gland.

High maternal genistein intake did not reduce offsprings breast cancer risk, and therefore high maternal soy intake in Asian women may not be associated with daughters low breast cancer risk.

Wu M, Harvey K, et al. Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway. Int J Cancer, May 17, 2005 [epub ahead of print]

The effect of fish oils and their active omega-3 fatty acid constituents, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were investigated on breast cancer growth.

In in vivo experiments, mice were fed diets that were rich in either omega-3 (fish oil) or omega-6 (corn oil) fatty acids. Three weeks after implantation of MDA-MB-231 breast cancer cells, the tumor volume and weight were significantly lower (p < 0.05) for mice fed the omega-3 diets compared to those fed the omega-6 diets.

Dietary fish oil also caused a 40% (p < 0.05) increase in neutral sphingomyelinase (N-SMYase) activity in the tumors. The tumor tissues from fish oil-fed animals expressed elevated p21 (waf1/cip1) mRNA, whereas tumor tissues from corn oil-fed animals exhibited undetectable levels of p21 expression.

In in vitro experiments, at concentrations as low as 25 muM, DHA and EPA inhibited the growth of cultured MDA-MB-231 cells in a dose-dependent manner by 20-25% (p < 0.05). N-SMYase activity was also increased by 30-40% (p < 0.05) in the DHA- or EPA-treated cells in which an increase in ceramide formation was observed.

DHA and EPA were both observed to enhance membrane bleb formation and also to induce the expression of p21. Omega-3 fatty acids-induced bleb formation and p21 expression were inhibited by the N-SMYase inhibitor GW4869, which also inhibited apoptosis by approximately 40% (p < 0.05).

The results suggest that inhibition of breast cancer growth in nude mice by dietary fish oil and inhibition of breast cancer cell growth in culture by treatment with DHA and EPA is mediated by activation of N-SMYase.

(c) 2005 Wiley-Liss, Inc.

PMID: 15900589

Menendez JA, Vellon L, et al. Effect of -Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene. J. Nat. Cancer Institute, 2005; 97 (21):1611-1615.

The omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA; 18:3n-6), which is found in several plant oils and is used as an herbal medicine, has antitumor activity in vitro.

We examined the effect of GLA on the expression of the Her-2/neu (erbB-2) oncogene, which is involved in development of numerous types of human cancer.
Flow cytometric and immunoblotting analyses demonstrated that GLA treatment substantially reduced Her-2/neu protein levels in the Her-2/neu overexpressing cell lines BT-474, SK-Br3, and MDA-MB-453 (breast cancer), SK-OV3 (ovarian cancer), and NCI-N87 (gastrointestinal tumor derived).

GLA exposure led to a dramatic decrease in Her-2/neu promoter activity and a concomitant increase in the levels of polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu, in these cell lines.

In transient transfection experiments, a Her-2/neu promoter bearing a PEA3 site mutated sequence was not subject to negative regulation by GLA in Her-2/neu overexpressing cell lines.

Concurrent treatments of Her-2/neu?overexpressing cancer cells with GLA and the anti Her-2/neu antibody trastuzumab led to synergistic increases in apoptosis and reduced growth and colony formation.

Hardman W. Omega-3 fatty acids to augment cancer therapy. J. Nutr 2002;132:3508S-3512S

The results of animal studies have demonstrated that the consumption of omega-3 fatty acids can slow the growth of cancer xenografts, increase the efficacy of chemotherapy and reduce the side effects of the chemotherapy or of the cancer.

Molecular mechanisms postulated to contribute to the multiple benefits of omega-3 fatty acids include:
1) suppressing the expression of cyclooxygenase-2 in tumors, thus decreasing proliferation of cancer cells and reducing angiogenesis in the tumor;
2) decreasing the expression of AP-1 and ras, two oncogenes implicated in tumor promotion;
3) inducing differentiation of cancer cells;
4) suppressing nuclear factor-B activation and bcl-2 expression, thus allowing apoptosis of cancer cells; and
5) reducing cancer-induced cachexia.

It seems reasonable to assume that after appropriate cancer therapy, consumption of omega-3 fatty acids might slow or stop the growth of metastatic cancer cells, increase longevity of cancer patients and improve their quality of life.

Hardman, WE. (n-3) Fatty Acids and Cancer Therapy. J. Nutr, 2004;134:3427S-3430S.

Supplementing the diet of tumor-bearing mice or rats with oils containing (n-3) (omega-3) or with purified (n-3) fatty acids has slowed the growth of various types of cancers, including lung, colon, mammary, and prostate.

The efficacy of cancer chemotherapy drugs such as doxorubicin, epirubicin, CPT-11, 5-fluorouracil, and tamoxifen, and of radiation therapy has been improved when the diet included (n-3) fatty acids.

Some potential mechanisms for the activity of (n-3) fatty acids against cancer include modulation of eicosanoid production and inflammation, angiogenesis, proliferation, susceptibility for apoptosis, and estrogen signaling.

In humans, (n-3) fatty acids have also been used to suppress cancer-associated cachexia and to improve the quality of life.

In one study, the response to chemotherapy therapy was better in breast cancer patients with higher levels of (n-3) fatty acids in adipose tissue [indicating past consumption of (n-3) fatty acids] than in patients with lower levels of (n-3) fatty acids.

Thus, in combination with standard treatments, supplementing the diet with (n-3) fatty acids may be a nontoxic means to improve cancer treatment outcomes and may slow or prevent recurrence of cancer.

Used alone, an (n-3) supplement may be a useful alternative therapy for patients who are not candidates for standard toxic cancer therapies.

Rose DP, Connolly JM, Rayburn J, Coleman M. Influence of diets containing eicosapentaenoic or docosahexaenoic acid on growth and metastasis of breast cancer cells in nude mice. J Natl Cancer Inst 1995;87(8):587-92.

BACKGROUND: Diets rich in omega-6 polyunsaturated fatty acids (e.g., corn oil and other fats containing linoleic acid) stimulate the growth and metastasis of human breast cancer cells in athymic nude mice. On the other hand, diets containing fish oil, which is rich in omega-3 fatty acids (e.g., eicosapentaenoic and docosahexaenoic acids), exert suppressive effects.

PURPOSE: Our objective was twofold: 1) to compare the effects of diets containing linoleic acid with those of diets containing eicosapentaenoic acid and docosahexaenoic acid on the growth and metastasis of MDA-MB-435 human breast cancer cells in the nude mouse model and 2) to determine how such effects relate to observed changes in the chemical content of tumor fatty acids and eicosanoid production.

METHODS: Groups of 30 female athymic nude mice were fed 20% (wt/wt) fat diets containing either linoleic acid (8%) alone, linoleic acid (8%) plus eicosapentaenoic acid (4%) or docosahexaenoic acid (4%), or linoleic acid (4%) plus eicosapentaenoic acid (8%) or docosahexaenoic acid (8%) for 7 days before one million MDA-MB-435 cells were injected into a thoracic mammary fat pad. Diets were continued for 12 more weeks. Primary tumors were measured weekly. The mice were then killed and necropsied, and tumor tissues preserved. Cell membrane phospholipid fatty acid analyses and eicosanoid assays were performed. All P values represent two-tailed tests of statistical significance.

RESULTS: The growth of the primary tumors was retarded in mice fed the diets supplemented with eicosapentaenoic or docosahexaenoic acid compared with the growth of primary tumors in mice fed the 8% linoleic acid diet. Growth inhibition was statistically significant (P < .05) and most effective in association with the diets containing 8% of either omega-3 fatty acid, where tumors were smaller than those in the group fed the diet containing 8% linoleic acid alone at all time points after the 2nd week. The occurrence and severity of lung metastases were reduced in the groups fed omega-3 fatty acid (P < .05). In groups of mice fed eicosapentaenoic or docosahexaenoic acid, the representation of these acids in tumor phospholipids increased, with a statistically significant reduction in the concentrations of arachidonic acid (all groups), tumor 12- and 15-hydroxyeicosatetraenoic acid, and prostaglandin E. Levels of 5-hydroxyeicosatetraenoic acid and leukotriene B4 were unaffected by the omega-3 fatty acids.

CONCLUSION: The inhibitory effects of dietary fish oil on human breast cancer cell growth and metastasis in this model system are ascribable to its high eicosapentaenoic acid and docosahexaenoic acid content; the mechanism very likely involves suppression of tumor eicosanoid biosynthesis.

IMPLICATION: Future dietary intervention trials designed to reduce the risk of recurrence in the postsurgical breast cancer patient should include the evaluation of eicosapentaenoic acid and docosahexaenoic acid supplementation.

Noguchi M, Rose D, Earashi M, et al. The role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma. Oncology 1995; 52(4): 265-271.

We have reviewed the literature concerning the role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma.

The omega-6 polyunsaturated fatty acids (PUFAs), primarily linoleic acid, promote breast cancer tumorigenesis and tumor cell proliferation directly and indirectly via increased synthesis of cyclooxygenase- and lipoxygenase-catalyzed products.

The omega-3 PUFAs, primarily docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), suppress breast carcinoma tumorigenesis and tumor cell proliferation, although the effect of DHA may be partly ascribed to increased amounts of EPA derived from DHA.
Both cyclooxygenase and lipoxygenase inhibitors suppress tumorigenesis and/or tumor proliferation, with the latter being more active.

Thus, arachidonic acid-derived eicosanoids play an important role in breast cancer, and the balance of the various eicosanoids may be a critical determinant of cell proliferation.

However, the exact mechanism by which fatty acids and eicosanoid synthesis inhibitors exert stimulatory and inhibitory effects on breast carcinoma is still not well understood.

Source: Oncology 1995 Jul-Aug;52(4):265-71