Dietary zinc deficiency or supplementation during gestation increases breast cancer susceptibility in adult female mice offspring following a J-shaped pattern and through distinct mechanisms.

Zinc is required for fetal development and is involved in key processes associated with breast carcinogenesis. We evaluated whether maternal zinc deficiency or supplementation during gestation influences female offspring susceptibility to breast cancer in adulthood. C57BL/6 mice consumed during gestation control (30 p.p.m. zinc), zinc-deficient (8 p.p.m) or zinc-supplemented (45 p.p.m.) diets. Maternal zinc supplementation increased in female mice offspring the incidence of chemically-induced mammary adenocarcinomas that were heavier, compared to control group. This was accompanied by a decreased number of terminal end buds, increased cell proliferation and apoptosis, and increased tumor suppressors p21, p53 and Rassf1, Zfp382 and Stat3 expression in mammary glands, as well as increased zinc status. Although maternal zinc deficiency did not alter the incidence of these lesions, it also induced heavier mammary adenocarcinomas, compared to control group. These effects were accompanied by a decreased number of terminal end buds, increased proto-oncogenes c-Myc and Lmo4 expression and H3K9Me3 and H4K20Me3 epigenetic marks in mammary glands of offspring, and decreased zinc status and increased levels of oxidative marker malondialdehyde. The data suggest that both maternal zinc deficiency and supplementation during gestation programmed increased breast cancer susceptibility in adult mice offspring following a J-shaped pattern through distinct mechanisms.

A high-corn-oil diet strongly stimulates mammary carcinogenesis, while a high-extra-virgin-olive-oil diet has a weak effect, through changes in metabolism, immune system function and proliferation/apoptosis pathways.

Breast cancer is the most common malignancy in women worldwide, and dietary lipids are important environmental factors influencing its etiology. We have investigated the effects, and the mechanisms associated, of high-fat diets on 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Animals were fed a low-fat, a high-corn-oil (HCO) or a high-extra-virgin-olive-oil (HOO) diet from weaning or after induction. The HCO diet had a clear stimulating effect on mammary carcinogenesis, especially when dietary intervention started after induction, whereas the tumors from HOO diet groups exhibited clinical and morphological characteristics similar to those from low-fat controls. Transcriptomic and further protein and immunohistochemical analyses of tumors also indicated different modulatory effects of high-fat diets affecting relevant biological functions: metabolism, immunosurveillance and proliferation/apoptosis pathways. Thus, the results suggested different metabolic adaptations with increased glycolysis by effect of HOO diet. Moreover, leukocyte tumor infiltration and inflammation mediators showed increased cytotoxic T cells and decreased TGFß1 expression by the HOO diet, while the HCO one increased arginase expression and IL-1α plasma levels. Furthermore, the study of proteins controlling proliferation/apoptosis pathways (Sema3A, Stat5, Smad1, Casp3) suggested an increase in proliferation by the HCO diet and an increase of apoptosis by the diet rich in olive oil. In conclusion, the HCO diet clearly stimulated mammary carcinogenesis, especially in the promotion phase, and induced molecular changes suggesting increased tumor proliferation/apoptosis balance and a proinflammatory microenvironment. The HOO diet, despite being high fat, had a weaker effect on tumorigenesis probably related to metabolic adaptations, enhanced immunosurveillance and increased apoptosis.

Paternal selenium deficiency but not supplementation during preconception alters mammary gland development and 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis in female rat offspring.

Breast cancer is a global public health problem and accumulating evidence indicates early-life exposures as relevant factors in the disease risk determination. Recent studies have shown that paternal nutrition can influence offspring health including breast cancer risk. Selenium is a micronutrient with essential role in central aspects of embryogenesis, male fertility and cancer and that has been extensively studied as a chemopreventive agent in several breast cancer experimental models. Thus, we designed an animal study to evaluate whether paternal selenium deficiency or supplementation during preconception could affect the female offspring mammary gland development and breast cancer susceptibility. Male Sprague-Dawley rats were fed AIN93-G diet containing 0.15 ppm (control diet), 0.05 ppm (deficient diet) or 1 ppm (supplemented diet) of selenium for 9 weeks and mated with control female rats. Mammary carcinogenesis was induced with 7,12-dimethylbenz[a]anthracene (DMBA) in their female offspring. Paternal selenium deficiency increased the number of terminal end buds, epithelial elongation and cell proliferation in the mammary gland of the female rat offspring and these effects were associated with higher susceptibility to DMBA-induced mammary tumors (increased incidence and higher grade tumors). On the other hand, paternal selenium supplementation did not influence any of these parameters. These results highlight the importance of father's nutrition including selenium status as a relevant factor affecting daughter's breast cancer risk and paternal preconception as a potential developmental stage to start disease preventive strategies.

Dietary extra-virgin olive oil and corn oil differentially modulate the mRNA expression of xenobiotic-metabolizing enzymes in the liver and in the mammary gland in a rat chemically induced breast cancer model.

High extra-virgin olive oil (EVOO) and corn oil diets differentially modulate experimental mammary carcinogenesis. We have investigated their influence on the initiation stage through the modulation of the expression of xenobiotic-metabolizing enzymes (XMEs) in the liver and the mammary gland. Female Sprague-Dawley rats were fed a low-fat (LF), high corn oil (HCO), or high EVOO (HOO) diet from weaning and gavaged with 7,12-dimethylbenz(a)anthracene (DMBA). The HCO diet increased the mRNA levels of the phase I enzymes CYP1A1, CYP1A2 and, to a lesser extent, CYP1B1, in the liver. The Aryl hydrocarbon receptor (AhR) seemed to be involved in this upregulated CYP1 expression. However, a slight trend toward an increase in the mRNA levels of the phase II enzymes GSTP1 and NQO1 was observed with the HOO diet. At least in the case of GSTP1, this effect was linked to an increased Nrf2 transactivation activity. This different regulation of the XMEs expression led, in the case of the HCO diet, to a balance between the production of active carcinogenic compounds and their inactivation tilted toward phase I, which would stimulate DMBA-induced cancer initiation, whereas the HOO diet was associated with a slower phase I metabolism accompanied by a faster phase II detoxification, thus reducing the output of the active compounds to the target tissues. In the mammary gland, the differential effects of diets may be conditioned by the state of cell differentiation, sexual maturity, and hormone metabolism.

A maternal high n-6 fat diet with fish oil supplementation during pregnancy and lactation in rats decreases breast cancer risk in the female offspring.

The timing of dietary fat intake may modify breast cancer risk. In addition, n-3 fatty acids reduce, and n-6 fatty acids increase, the risk of breast cancer and a maternal high n-6 fat diet results in a greater risk of breast cancer in the female offspring. We hypothesized that the timing of n-3 fatty acid-enriched fish oil supplementation would be important for reducing the risk of breast cancer. Female rats were fed to a high n-6 fat diet containing 20% of the sunflower oil by weight during pregnancy and lactation, and the female offspring were exposed to fish oil by oral gavage either during the perinatal period via maternal intake or during puberty or adulthood. Exposure during the perinatal period to a maternal high n-6 fat diet with fish oil supplementation significantly reduced the incidence of carcinogen-induced mammary tumors in the female offspring compared to a maternal high n-6 fat diet with no fish oil supplementation or fish oil supplementation later in life (P=.0228 by Cox proportional hazards model). We found that a maternal high n-6 fat diet during pregnancy is more important in increasing the risk of mammary tumors in the female offspring than a maternal high n-6 fat diet during lactation. This study suggests that fish oil supplementation during the perinatal period decreases the effect of a maternal high n-6 fat diet on subsequent carcinogen-induced mammary tumor risk, whereas fish oil supplementation during puberty or adulthood does not.

[Dietary fatty acids and experimental carcinogenesis]. / Acides gras alimentaires et cancérogenèse: données expérimentales in vivo.

Experiments in animal models of mammary carcinogenesis suggest that fatty acids promote mammary tumors development. This effect depends first on the amount then on the type of fatty acids available. n-6 fatty acids such as linoleic acid generally stimulates mammary tumor growth, while n-3 fatty acids oppose this effect. Conjugated diene fatty acids (CLA) inhibit mammary carcinogenesis when brought at elevated amount. There are limitations in using an animal model in the analysis between nutrition and colorectal cancers. This is ascribable to the following: firstly, the digestive tract of rodents if different from that of humans and secondly, the induction of colon cancer in these animals (chemical carcinogenesis, injection of cancerous cells or transgenesis) does not mimic human colon carcinogenesis. However, on the basis of numerous published data, some important correlations have arisen that could generate hypotheses and guide new epidemiological/interventional and experimental studies. In these animal models it appears that an adequate supply of n-3 PUFAs and oleic acid in food may exert a protective effect at all stages of colon carcinogenesis. On the other hand, an excessive consumption of n-6 PUFAs and of saturated fatty acids could promote colon cancers.

Flor-Essence herbal tonic does not inhibit mammary tumor development in Sprague Dawley rats.

BACKGROUND: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. METHODS: Female Sprague-Dawley rats were given water or exposed to 3 or 6% Flor-Essence beginning at 1 day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethyl-benz[a]anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. RESULTS: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0 and 59.4% for the 3 and 6% Flor-Essence groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0 and 97.3% for rats consuming 3 and 6% Flor-Essence, respectively. Mean mammary tumor multiplicity (+/-SES) for the controls was 2.8 (+/-0.5) and statistically different from the 3 or 6% Flor-Essence groups with 5.2 (+/-0.7), and 4.8 (+/-0.6), respectively (p < or = 0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. CONCLUSIONS: Flor-Essence can promote mammary tumor development in the Sprague-Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

Treatment of 1-methyl-1-nitrosourea-induced mammary tumours with immunostimulatory CpG motifs and 13-cis retinoic acid in female rats: histopathological study.

Histopathological evaluation of the mammary gland tumours of Sprague-Dawley rats induced with 1-methyl-1-nitrosourea (MNU), and treated with either CpG oligodeoxynucleotides (CpG-ODN) and/or 13-cis retinoic acid has been performed in this work. Since, the treatment of animals with CpG-ODN induced a significant decrease of tumour burden and volume in comparison with MNU treated control group (Macejova et al. 2001), it was of high impact to compare histological appearance of tumours in different experimental groups (MNU, CpG-ODN, 13-cis retinoic acid, CpG-ODN plus 13-cis retinoic acid). We have found reduced number of carcinomas with necroses in the CpG motifs treated group when compared to animals treated with MNU only. From the histological point of view the treatment with the CpG-ODN may have some protective effect. Carcinoma patterns proportion in the group treated with CpG-ODN was found to be different in comparison with other experimental groups. Treatment of rats with CpG-ODN had no apparent effect on invasiveness of developed carcinomas.

Hormonal and dietary modulation of mammary carcinogenesis in mouse mammary tumor virus-c-erbB-2 transgenic mice.

Exogenous and dietary estrogens have been associated with modification of breast cancer risk. Mammary cancer model systems can be used to explore interactions between specific transgenes, and hormonal and dietary factors. Transgenic mice bearing the rat wild-type erbB-2 gene were used to study the effects of short-term hormonal exposure [17beta-estradiol (E2) or tamoxifen] or a soy meal diet on mammary carcinogenesis. In mice fed a casein diet, mammary tumors developed at an earlier age after short-term E2 exposure during the early reproductive period. The median mammary tumor latency was shortest (29 weeks) for the high-dose estrogen as compared with the lowest dose of E2 treated or placebo control mice (33 and 37 weeks, respectively). The timing of short-term E2 exposure was also important, with the most significant changes observed in mice exposed to E2 between 8 and 18 weeks of age. E2 exposure was associated with the subsequent development of more aggressive tumors as determined by histologic grade, multifocal tumor development, stromal invasion, and pulmonary metastasis. In contrast, short-term tamoxifen-exposed mice generally failed to develop mammary tumors by 60 weeks of age. Mice fed a soy meal diet developed mammary tumors at a later age than casein-fed animals treated with E2 or placebo, whereas no differences were observed by diet for the tamoxifen-treated mice. Mammary tumor prevention was >80% in tamoxifen-treated mice on either diet. Novel histologic tumor types were identified, suggesting greater phenotypic diversity than described previously. Benign mammary gland morphogenesis was also significantly altered by short-term hormonal exposure or dietary factors, consistent with the modification of mammary tumor risk in specific treatment groups. Estrogenic modulation of the mammary tumor phenotype in wild-type erbB-2 transgenic mice was observed. Histologic tumor types and clinical aggressivity not reported previously in this transgenic model were noted, suggesting greater biologic heterogeneity than reported previously. In addition, dietary phytoestrogens modified mammary development and tumor latency, suggesting a need for greater stringency in dietary assignment for transgenic mouse models of mammary neoplasia.

Pre-clinical applications of transgenic mouse mammary cancer models.

Breast cancer is a leading cause of cancer morbidity and mortality. Given that the majority of human breast cancers appear to be due to non-genetic factors, identifying agents and mechanisms of prevention is key to lowering the incidence of cancer. Genetically engineered mouse models of mammary cancer have been important in elucidating molecular pathways and signaling events associated with the initiation, promotion, and the progression of cancer. Since several transgenic mammary models of human breast cancer progress through well-defined cancer stages, they are useful pre-clinical systems to test the efficacy of chemopreventive and chemotherapeutic agents. This review outlines several oncogenic pathways through which mammary cancer can be induced in transgenic models and describes several types of preventive and therapeutic agents that have been tested in transgenic models of mammary cancer. The effectiveness of farnesyl inhibitors, aromatase inhibitors, differentiating agents, polyamine inhibitors, anti-angiogenic inhibitors, and immunotherapeutic compounds including vaccines have been evaluated in reducing mammary cancer and tumor progression in transgenic models.

A preliminary study on the carcinogenicity of the common fern Onychium contiguum.

Onychium contiguum (Family Cryptogrammaceae) is a common terrestrial fern in the Himalayas and in many other parts of the world. It is also present on the pastures in areas where grazing animals suffer from bovine urinary bladder cancer. This fern is occasionally grazed by animals and in some areas it is present as a contaminant in grasses stored for winter feeding. Certain species of the genus Onychium are used in folk medicine. Long-term exposure of experimental animals to O. contiguum appeared to cause tumours of the ileum. urinary bladder and mammary glands.

Potent preventive action of curcumin on radiation-induced initiation of mammary tumorigenesis in rats.

This investigation evaluated the preventive effect of curcumin on radiation-induced tumor initiation in rat mammary glands. Fifty-four female rats were mated and then divided into two groups at day 11 of pregnancy. As the control group, 27 rats were fed a basal diet during the experimental period. As the experimental group, 27 rats were fed a diet containing 1% curcumin between day 11 of pregnancy and parturition (day 23 of pregnancy). All rats of both groups received whole body irradiation with 1.5 Gy gamma-rays from a (60)Co source at day 20 of pregnancy and were then implanted with a diethylstilbestrol pellet 1 month after weaning. A high incidence (70.3%) of mammary tumorigenesis was observed in the control group. The tumor incidence (18.5%) was significantly reduced in the rats fed curcumin during the initiation stage. The appearance of the first palpable tumor was delayed by 6 months in the curcumin-fed group and the average latent period until the appearance of mammary tumors was 2.5 months longer in the curcumin-fed group than in the control group. By histological examination, the proportion of adenocarcinoma (16.7%) in total tumors in the curcumin-fed rats was found to be decreased to half that (32.1%) in the control group. Compared with the control rats, the body weight of rats in the experimental group was decreased slightly by administration of the curcumin diet from day 11 of pregnancy, in spite of a similar intake of diet, but had recovered to the level of the control by the end of the experiment. At the time of irradiation, curcumin did not have any effect on organ weight or on the development and differentiation of mammary glands of pregnant rats. In addition, the serum concentrations of fatty acids, thiobarbituric acid-reactive substances and ovarian and pituitary hormones, except LH, remained at the control level. Also, no change in litter size and body weight of pups born from curcumin-fed rats indicated no toxicity of curcumin. These results suggest that curcumin does not have any side-effects and is an effective agent for chemoprevention acting at the radiation-induced initiation stage of mammary tumorigenesis.

Effect of dietary soy isoflavone aglycones on the urinary 16alpha-to-2-hydroxyestrone ratio in C3H/HeJ mice.

Estradiol is metabolized through two mutually exclusive pathways. 2-Hydroxyestrone (2-OHE,) is antiestrogenic, while 16alpha-hydroxyestrone (16alpha-OHE1) is a potent estrogen. It is suggested that a high urinary 16alpha-OHE1-to-2-OHE1 rato is a biomarker of increased mammary tumor risk. Mice were fed one of the test diets for 21 days. Indole-3-carbinol (2,500 mg/kg diet) increased the cytochrome P-450 content of hepatic microsomes and liver weight and reduced the urinary 16alpha-OHE1-to-2-OHE1 ratio in comparison with the respective value in the control mice. Fermented soy extract (100, 200, or 400 mg isoflavonoid/kg diet), genistein (200 mg/kg diet), and daidzein (200 mg/kg diet) each reduced the urinary 16alpha-OHE1-to-2-OHE1 ratio without increasing the cytochrome P-450 content of hepatic microsomes or liver weight. The combination of genistein and daidzein (100 mg and 100 mg/kg diet) did not have a synergistic effect on the reduction in urinary 16alpha-OHE1-to-2-OHE1 ratio. These data suggest that the soy isoflavonoid aglycones genistein and daidzein and indole-3-carbinol each exert a cancer-preventive effect by shifting metabolism away from the production of genotoxic metabolites toward the production of inactive metabolites.

Effects of simultaneous treatment with hydroxyapatite and coffee cherry, the residue left after the removal of coffee beans, on spontaneous mammary tumourigenesis and related parameters in SHN mice.

We have found that the chronic administration of the diet containing 5% hydroxyapatite (HAP) derived from bovine or swine bone or drinking water containing 0.5% extract of coffee cherry (CC), the residue left after the removal of coffee beans, induced a marked inhibition of spontaneous mammary tumourigenesis in SHN mice, while the effects decreased with age. In the present study, the combined effects of HAP and CC on mammary tumourigenesis and related parameters were examined. The inhibitory effects of HAP or CC alone on the development and/or the growth of mammary tumours were reduced by HAP + CC. Decreased food and water intake and retarded body growth caused by CC were ameliorated by HAP. Enhancement by HAP or CC of the excretion of the urine components was mostly nullified by HAP + CC. Parameters such as normal mammary gland growth and uterine adenomyosis on which neither HAP nor CC had an effect also did not respond to HAP + CC. These findings suggest that the target is important when administering natural products in combination if the agents are to manifest their effects, additive, synergistic, antagonistic or otherwise.

Effects of reduced dietary linoleic acid intake, alone or combined with an algal source of docosahexaenoic acid, on MDA-MB-231 breast cancer cell growth and apoptosis in nude mice.

Diets rich in linoleic acid (LA), an n-6 fatty acid, stimulate the progression of human breast cancer cell solid tumors in athymic nude mice, whereas docosahexaenoic acid (DHA) and eicosapentaenoic acid, long-chain n-3 fatty acids, exert suppressive effects. In the present study we used a novel source of DHA, in triglyceride form, to determine the effects of feeding low levels of the fatty acid on the growth of MDA-MB-231 cells injected into the thoracic mammary fat pads of female nude mice. Four different isocaloric diets were used, all of which provided 20% (wt/wt) total fat. The control diets contained 8% (20 mice) or 4% (50 mice) LA; the n-3 fatty acid-supplemented groups of 50 mice were fed 4% LA-containing diets plus 2% or 4% DHA. The tumor growth rates were reduced significantly in mice fed the 4% LA compared with the 8% LA diet; the addition of 4% DHA to the 4% LA-containing diet produced a further reduction in tumor growth rate (p < or = 0.003 at and after Week 6). The final tumor weights were also reduced in the DHA-fed mice compared with the 8% LA dietary group (2% DHA, p = 0.02; 4% DHA, p = 0.01) and in the 4% DHA-fed mice compared with the 4% LA control group (p = 0.02); a similar trend for mice fed the lower level of DHA did not achieve statistical significance. Tumor prostaglandin E2 concentrations were reduced by feeding the lower LA level; further dose-dependent decreases occurred in the DHA dietary groups and were accompanied by reduced levels of 12- and 15-hydroxyeicosatetraenoic acids. These changes in eicosanoid biosynthesis may have been responsible for the observed decreases in cell proliferation, indicated by suppressed Ki-67 expression, and increases in apoptotic activity, as reflected in TdT-mediated dUTP nick end labeling immunohistochemical staining.

Black tea and mammary gland carcinogenesis by 7,12-dimethylbenz[a]anthracene in rats fed control or high fat diets.

Epidemiological studies suggest that tea may reduce cancer risk, and in laboratory rodents, chemopreventive effects of tea or purified extracts of tea have been demonstrated in lung, gastrointestinal tract and skin. There is some evidence of chemoprevention by tea in the mammary gland, but the data are not conclusive. In order to evaluate more fully the possible influence of black tea on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary gland tumors in the female S-D (Sprague-Dawley) rat, three large studies were performed: experiment 1, tumorigenesis in rats fed AIN-76A diet and given 25 mg/kg DMBA and 1.25 or 2.5% whole tea extract or water to drink; experiment 2, tumorigenesis in rats given 15 mg/kg DMBA and the same diet and fluids as in experiment 1; experiment 3, tumorigenesis in rats fed control or HF (high fat, corn oil) diet and given 15 mg/kg DMBA and 2% tea or water to drink. Tea was given throughout the experiment; DMBA was given by gastric gavage at 8 weeks of age. There was no consistent effect of tea on tumorigenesis in rats fed AIN-76A diet; there was, however, evidence in experiment 3 of a reduction of tumorigenesis by tea in rats fed the HF diet. In experiment 3, rats fed the HF diet and given water showed the expected increase in tumor burden (number and weight) compared with rats fed control diet. However, rats fed the HF diet and given 2% tea showed no increase in tumor burden; their tumor burden was significantly lower than in rats fed the HF diet and given water (P < 0.01) and was not different from rats fed control diet and given water or tea. In addition, in experiment 3, the number of malignant tumors per tumor-bearing rat was increased by the HF diet in water-drinking rats (P < 0.01) but not in tea-drinking rats. Therefore, it appears that tea partially blocked the promotion of DMBA-induced mammary tumorigenesis by the HF diet.

Involvement of tyrosine phosphorylation of p185(c-erbB2/neu) in tumorigenicity induced by X-rays and the neu oncogene in human breast epithelial cells.

Ionizing radiation is the exogenous agent best proven to induce breast cancer. c-erbB2/neu amplification and overexpression are known to occur in breast cancer and are correlated with aggressive tumor growth and poor prognosis. We have developed simian virus 40-immortalized cell lines from normal human breast epithelial cells (HBECs) with luminal and stem-cell characteristics. In this study, we examined whether x-rays and a mutated neu oncogene are capable of inducing tumorigenicity in these cells. The results indicated that x-rays were effective in converting immortal non-tumorigenic HBECs to weakly tumorigenic cells that then could be transformed to highly tumorigenic cells by the neu oncogene. The in vitro growth of these tumorigenic cells was significantly faster than that of the parental non-tumorigenic cells in growth factor- and hormone-supplemented or -depleted media. The neu oncogene, however, had no tumorigenic effect on immortal non-tumorigenic cells. The expression of p185(c-erb82/neu) was elevated in neu-transduced immortal or weakly tumorigenic cell lines. However, only in the latter was p185(c-erbB2/neu) found to be phosphorylated at tyrosine residues. Thus, x-rays appear to induce a genetic alteration that confers weak tumorigenicity on immortal HBECs and interacts with p185(c-erbB2/neu) directly or indirectly to give rise to fast-growing tumors.

Review of the effects of trans fatty acids, oleic acid, n-3 polyunsaturated fatty acids, and conjugated linoleic acid on mammary carcinogenesis in animals.

I review the effects of trans fatty acids, oleic acid, n-3 polyunsaturated fatty acids, and conjugated linoleic acid on mammary carcinogenesis in animals. The goal is not to provide an exhaustive survey of all the publications on these topics; such a Herculean effort has been accomplished by previous reviews, which are cited in the text. Instead, the emphasis is on the consistency or lack of consistency of information regarding each of the above fatty acids, confounding factors that may help to reconcile discrepancies in the database, a perspective of the history of the research, and certain unique or exciting opportunities that are worthy of special attention in evaluations of the relations between specific fatty acids and cancer. This review arrives at four conclusions: 1) There is little evidence that trans fatty acids have an adverse effect on carcinogenesis. 2) The data on cancer protection by oleic acid are not convincing. An inhibitory effect attributed to an increased intake of oleic acid could be due to an inadequate supply of linoleic acid. 3) Although a suppressive response to n-3 polyunsaturated fatty acids is observed in most cases, the availability of linoleic acid is likely to be a confounding factor in determining the final outcome. 4) Conjugated linoleic acid is unique in the sense that concentrations < or = 1% are sufficient for producing significant cancer protection and that this effect seems to be independent of the other fatty acids.