Body weight gain and control: beneficial effect of extra virgin olive oil versus corn oil in an experimental model of mammary cancer.

Obesity is a known risk factor for breast cancer, the most common malignancy among women worldwide. We have previously described different effects of high-fat diets on mammary experimental carcinogenesis. In this work, we analyzed the animal growth data obtained in six experimental assays, in healthy and carcinogen-induced rats undergoing different dietary interventions. The animals were fed with three experimental diets administered at different periods of development: a control low-fat diet, and two isocaloric high-fat diets (rich in corn oil or in extravirgin olive oil -EVOO-). Weekly weight throughout the development of 818 animals have been compiled and reanalyzed using adjusted mathematical models. Molecular mechanisms have been investigated: ethanolamides in small intestine, neuropeptides controlling satiety in hypothalamus, and proteins controlling lipid metabolism in adipose and mammary tissues. The results indicated that the effect of diets depended on type of lipid, timing of intervention and health status. The high corn oil diet, but not the high EVOO diet, increased body weight and mass, especially if administered from weaning, in healthy animals and in those that received a moderate dose of carcinogen. The potential protective effect of EVOO on weight maintenance may be related to anorexigenic neuropeptides such as oxytocin and lipolysis/deposition balance in adipose tissue (increasing phospho-PKA, HSL, MGL and decreasing FAS). In animals with cancer, body weight gain was related to the severity of the disease. Taken together, our results suggest that EVOO has a beneficial effect on body weight maintenance in both health and cancer.

Behavioral and Metabolic Effects of a Calorie-Restricted Cafeteria Diet and Oleuropein Supplementation in Obese Male Rats.

Diet-induced obesity models are widely used to investigate dietary interventions for treating obesity. This study was aimed to test whether a dietary intervention based on a calorie-restricted cafeteria diet (CAF-R) and a polyphenolic compound (Oleuropein, OLE) supplementation modified sucrose intake, preference, and taste reactivity in cafeteria diet (CAF)-induced obese rats. CAF diet consists of high-energy, highly palatable human foods. Male rats fed standard chow (STD) or CAF diet were compared with obese rats fed CAF-R diet, alone or supplemented with an olive tree leaves extract (25 mg/kg*day) containing a 20.1% of OLE (CAF-RO). Biometric, food consumption, and serum parameters were measured. CAF diet increased body weight, food and energy consumption and obesity-associated metabolic parameters. CAF-R and CAF-RO diets significantly attenuated body weight gain and BMI, diminished food and energy intake and improved biochemical parameters such as triacylglycerides and insulin resistance which did not differ between CAF-RO and STD groups. The three cafeteria groups diminished sucrose intake and preference compared to STD group. CAF-RO also diminished the hedonic responses for the high sucrose concentrations compared with the other groups. These results indicate that CAF-R diet may be an efficient strategy to restore obesity-associated alterations, whilst OLE supplementation seems to have an additional beneficial effect on sweet taste function.

Effects of diets high in corn oil or in extra virgin olive oil on oxidative stress in an experimental model of breast cancer.

Experimental evidence highlights the importance of dietetic factors on breast cancer. In this work we aimed to analyze the effects two oils, corn oil (rich in n-6 polyunsaturated fatty acids -PUFA-) and extra virgin olive oil (EVOO), on oxidative stress in an animal model of breast carcinogenesis. Female rats were fed a low-fat control, a high-corn oil, or a high-EVOO diet from weaning or after induction with 7,12-dimethylbenz[a]anthracene at 53 days. Animals were euthanized at 36, 51, 100 and 246 days of age. We analyzed antioxidant enzymes (mRNA and activity of superoxide dismutase, glutathione peroxidase and catalase), non-enzymatic capacity (oxidized and reduced glutathione) and DNA damage (8-oxo-dG) in tumors and mammary gland at different ages. We also analyzed lipid peroxidation (isoprostanes in serum and lipofuscin in liver). Results indicated a decrease in the enzymatic antioxidant capacity and increased oxidative stress in mammary gland of healthy young animals after a short period of high-fat diets intake, followed by an adaptation to chronic dietary intervention. After induction both diets, especially the one high in n-6 PUFA, increased the oxidized glutathione. In tumors no clear effects of the high-fat diets were observed, although in the long-term lipofuscin and 8-oxo-dG suggested greater oxidative damage by effect of the n-6 PUFA-rich diet. Considering the differential effects of these diets on mammary carcinogenesis that we have previously reported, this study suggests that these high-fat diets could have an effect on oxidative stress that would lead to different signaling pathways.

Dietary lipids differentially modulate the initiation of experimental breast carcinogenesis through their influence on hepatic xenobiotic metabolism and DNA damage in the mammary gland.

Breast cancer is the most common malignancy among women worldwide. In addition to reproductive factors, environmental factors such as nutrition and xenobiotic exposure have a role in the etiology of this malignancy. A stimulating and a potentially protective effect on experimental breast cancer has been previously described for high corn oil and high extra-virgin olive oil diets, respectively. This work investigates the effect of these lipids on the metabolism of 7,12-dimethylbenz(a)anthracene (DMBA), a polycyclic aromatic hydrocarbon that can initiate carcinogenesis and its consequences in an experimental rat breast cancer model. The PUFA n-6-enriched diet increased expression of Phase I enzymes prior to DMBA administration and raised the activity of CYP1s in the hours immediately after induction, while reducing the activity of Phase II enzymes, mainly NQO1. The levels of reactive metabolites measured in plasma by GC-MS and DMBA-DNA adducts in the mammary gland of the animals fed the high corn oil diet were also higher than in the other groups. On the other hand, the high extra-virgin olive oil diet and the control low-fat diet exhibited better coordinated Phase I and Phase II activity, with a lower production of reactive metabolites and less DNA damage in the mammary gland. The concordance between these effects and the different efficacy of the carcinogenesis process due to the dietary treatment suggest that lipids may differently modify mammary gland susceptibility or resistance to cancer initiation over the exposure to environmental carcinogens. SUMMARY: Dietary lipids influence the initiation of DMBA-induced mammary cancer through the modulation of liver xenobiotic metabolism, formation of reactive metabolites and subsequent DNA damage in the target tissue.

Diets high in corn oil or extra-virgin olive oil differentially modify the gene expression profile of the mammary gland and influence experimental breast cancer susceptibility.

PURPOSE: Nutritional factors, especially dietary lipids, may have a role in the etiology of breast cancer. We aimed to analyze the effects of high-fat diets on the susceptibility of the mammary gland to experimental malignant transformation. METHODS: Female Sprague-Dawley rats were fed a low-fat, high-corn-oil, or high-extra-virgin olive oil (EVOO) diet from weaning or from induction. Animals were induced with 7,12-dimethylbenz[a]anthracene at 53 days and euthanized at 36, 51, 100 and 246 days. Gene expression profiles of mammary glands were determined by microarrays. Further molecular analyses were performed by real-time PCR, TUNEL and immunohistochemistry. Carcinogenesis parameters were determined at 105 and 246 days. RESULTS: High-corn-oil diet increased body weight and mass when administered from weaning. The EVOO diet did not modify these parameters and increased the hepatic expression of UCP2, suggesting a decrease in intake/expenditure balance. Both diets differentially modified the gene expression profile of the mammary gland, especially after short dietary intervention. Corn oil down-regulated the expression of genes related to immune system and apoptosis, whereas EVOO modified the expression of metabolism genes. Further analysis suggested an increase in proliferation and lower apoptosis in the mammary glands by effect of the high-corn-oil diet, which may be one of the mechanisms of its clear stimulating effect on carcinogenesis. CONCLUSIONS: The high-corn-oil diet strongly stimulates mammary tumorigenesis in association with modifications in the expression profile and an increased proliferation/apoptosis balance of the mammary gland.

The Role of Dietary Extra Virgin Olive Oil and Corn Oil on the Alteration of Epigenetic Patterns in the Rat DMBA-Induced Breast Cancer Model.

Disruption of epigenetic patterns is a major change occurring in all types of cancers. Such alterations are characterized by global DNA hypomethylation, gene-promoter hypermethylation and aberrant histone modifications, and may be modified by environment. Nutritional factors, and especially dietary lipids, have a role in the etiology of breast cancer. Thus, we aimed to analyze the influence of different high fat diets on DNA methylation and histone modifications in the rat dimethylbenz(a)anthracene (DMBA)-induced breast cancer model. Female Sprague-Dawley rats were fed a low-fat, a high corn-oil or a high extra-virgin olive oil (EVOO) diet from weaning or from induction with DMBA. In mammary glands and tumors we analyzed global and gene specific (RASSF1A, TIMP3) DNA methylation by LUMA and bisulfite pyrosequencing assays, respectively. We also determined gene expression and enzymatic activity of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) and evaluated changes in histone modifications (H3K4me2, H3K27me3, H4K20me3 and H4K16ac) by western-blot. Our results showed variations along time in the global DNA methylation of the mammary gland displaying decreases at puberty and with aging. The olive oil-enriched diet, on the one hand, increased the levels of global DNA methylation in mammary gland and tumor, and on the other, changed histone modifications patterns. The corn oil-enriched diet increased DNA methyltransferase activity in both tissues, resulting in an increase in the promoter methylation of the tumor suppressor genes RASSF1A and TIMP3. These results suggest a differential effect of the high fat diets on epigenetic patterns with a relevant role in the neoplastic transformation, which could be one of the mechanisms of their differential promoter effect, clearly stimulating for the high corn-oil diet and with a weaker influence for the high EVOO diet, on breast cancer progression.

[CONSENSUS ON FATS AND OILS IN THE DIET OF S ISH ADULTS; POSITION PAPER OF THE SPANISH FEDERATION OF FOOD, NUTRITION AND DIETETICS SOCIETIES]. / CONSENSO SOBRE LAS GRASAS Y ACEITES EN LA ALIMENTACIÓN DE LA POBLACIÓN ESPAÑOLA ADULTA; POSTURA DE LA FEDERACIÓN ESPAÑOLA DE SOCIEDADES DE ALIMENTACIÓN, NUTRICIÓN Y DIETÉTICA (FESNAD).

The quality of dietary fat critically influences health. In this consensus document the scientific evidence relating effects of dietary fat quantity and quality on cardiovascular risk is reviewed and recommendations for the Spanish adult population are issued. As a novelty in nutrition guidelines, emphasis is made more on parent foods than on fatty acids per se. In summary, replacing saturated fatty acids (SFA) for monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) reduces cardiovascular risk. Recent data suggest that SFA proper may be harmful or not depending on the parent food, a reason why an intake threshold is not established, but consumption of foods containing excess SFA, such as butter, some processed meats, and commercial confectionery and fried foods is discouraged. The established threshold of <1 % of energy intake as trans FA, well known to be harmful for cardiovascular risk, is fulfilled in Spain due in part to its present low levels in margarines. MUFA are beneficial or neutral for cardiovascular risk depending on their dietary sources (virgin olive oil versus other fats), and no intake limitations are established.n-6 PUFA are cardioprotective and recommended intakes (5-10 % of energy) are not always fulfilled in the Spanish population, thus increased consumption of their vegetable food sources (seeds, derived oils, and margarines)is encouraged. Marine n-3 PUFA are also cardioprotective and the recommendation stands to eat fatty fish≥2 servings/weeks to reach intake levels of at least 250 mg/day. Increasing evidence suggests that alpha-linolenic acid (ALA), the vegetable n-3 PUFA, is also cardioprotective,but the parent foods (walnuts, soy products,green-leaf vegetables) may provide benefits beyond ALA itself. Finally, low-fat (high carbohydrate, particularly when having a high glycemic index) diets appear to lack cardiovascular preventive effects, while high-fat,high-vegetable fat dietary patterns such as the Mediterranean diet, are protective, a reason why no upper limit on fat intake is established for the Spanish population.This position statement targets dietitians, nutritionists and other health professionals involved in dietary counsel so they can deliver it rightly and according to the last scientific evidence.

La calidad de la grasa dietética tiene una profunda influencia sobre la salud. En este documento de consenso se evalúa la evidencia científica relativa a los efectos de la cantidad y calidad de la grasa alimentaria sobre la salud cardiovascular y se emiten recomendaciones para la población española adulta. Como novedad en unas guías nutricionales, se hace menos hincapié en los ácidos grasos per se que en los alimentos que los contienen. En resumen, sustituir ácidos grasos saturados (AGS) por monoinsaturados (AGM) y poliinsaturados (AGP) reduce el riesgo cardiovascular. Datos recientes sugieren que la ingesta de AGS per se es nociva solo en función del alimento que los contiene, por lo que no parece oportuno establecer un umbral de ingesta, pero se desaconsejan alimentos que los contienen en exceso, como la mantequilla y algunos derivados cárnicos, bollería y fritos comerciales. El límite de.

Consenso sobre las grasas y aceites en la alimentación de la población española adulta; postura de la Federación Española de Sociedades de Alimentación, Nutrición y Dietética (FESNAD) / Consensus on fats and oils in the diet of spanish adults; position paper of the spanish federation of food, nutrition and dietetics societies

La calidad de la grasa dietética tiene una profunda influencia sobre la salud. En este documento de consenso se evalúa la evidencia científica relativa a los efectos de la cantidad y calidad de la grasa alimentaria sobre la salud cardiovascular y se emiten recomendaciones para la población española adulta. Como novedad en unas guías nutricionales, se hace menos hincapié en los ácidos grasos per se que en los alimentos que los contienen. En resumen, sustituir ácidos grasos saturados (AGS) por monoinsaturados (AGM) y poliinsaturados (AGP) reduce el riesgo cardiovascular. Datos recientes sugieren que la ingesta de AGS per se es nociva solo en función del alimento que los contiene, por lo que no parece oportuno establecer un umbral de ingesta, pero se desaconsejan alimentos que los contienen en exceso, como la mantequilla y algunos derivados cárnicos, bollería y fritos comerciales. El límite de su bajo nivel actual en las margarinas. Los AGM son beneficiosos o neutros para el riesgo cardiovascular según su fuente dietética (aceite de oliva virgen frente a otras grasas), y no se establecen limitaciones de ingesta. Los AGP n-6 son cardioprotectores y el nivel recomendable de ingesta (5-10 % de la energía) no siempre se cumple en la población española, que debería aumentar el consumo de sus fuentes vegetales (semillas, aceites derivados y margarinas). Los AGP n-3 de origen marino son cardioprotectores y se recomienda consumir pescado graso ≥2 veces/semana para cumplir con la recomendación de al menos 250 mg/día. Existen evidencias crecientes de que el ácido alfa-linolénico (ALA), el AGP n-3 de origen vegetal, también es cardioprotector, pero los alimentos que lo contienen (nueces, soja, vegetales de hoja verde) pueden ser beneficiosos más allá del propio ALA. Finalmente, las dietas bajas en grasa (altas en hidratos de carbono, particularmente aquellas con un alto índice glicémico) carecen de efecto preventivo cardiovascular, mientras que las altas en grasa de origen vegetal, como la dieta mediterránea, son protectoras, razón por la que en España no parece necesario establecer un dintel superior de ingesta de grasa. Este documento de consenso se dirige a dietistas, nutricionistas y otros profesionales que dan consejo dietético para que puedan hacerlo de una manera razonada y acorde con la última evidencia científica (AU)

The quality of dietary fat critically influences health. In this consensus document the scientific evidence relating effects of dietary fat quantity and quality on cardiovascular risk is reviewed and recommendations for the Spanish adult population are issued. As a novelty in nutrition guidelines, emphasis is made more on parent foods than on fatty acids per se. In summary, replacing saturated fatty acids (SFA) for monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) reduces cardiovascular risk. Recent data suggest that SFA proper may be harmful or not depending on the parent food, a reason why an intake threshold is not established, but consumption of foods containing excess SFA, such as butter, some processed meats, and commercial confectionery and fried foods is discouraged. The established threshold of known to be harmful for cardiovascular risk, is fulfilled in Spain due in part to its present low levels in margarines. MUFA are beneficial or neutral for cardiovascular risk depending on their dietary sources (virgin olive oil versus other fats), and no intake limitations are established. n-6 PUFA are cardioprotective and recommended intakes (5-10 % of energy) are not always fulfilled in the Spanish population, thus increased consumption of their vegetable food sources (seeds, derived oils, and margarines) is encouraged. Marine n-3 PUFA are also cardioprotective and the recommendation stands to eat fatty fish ≥2 servings/weeks to reach intake levels of at least 250 mg/day. Increasing evidence suggests that alpha-linolenic acid (ALA), the vegetable n-3 PUFA, is also cardioprotective, but the parent foods (walnuts, soy products, green-leaf vegetables) may provide benefits beyond ALA itself. Finally, low-fat (high carbohydrate, particularly when having a high glycemic index) diets appear to lack cardiovascular preventive effects, while high-fat, high-vegetable fat dietary patterns such as the Mediterranean diet, are protective, a reason why no upper limit on fat intake is established for the Spanish population. This position statement targets dietitians, nutritionists and other health professionals involved in dietary counsel so they can deliver it rightly and according to the last scientific evidence (AU)

Effect of High Fat Diets on Body Mass, Oleylethanolamide Plasma Levels and Oxytocin Expression in Growing Rats.

Obesity prevalence in developed countries has promoted the need to identify the mechanisms involved in control of feeding and energy balance. We have tested the hypothesis that different fats present in diet composition may contribute in body weight gain and body indexes by regulation of oxytocin gene (oxt) expression in hypothalamus and Oleylethanolamide (OEA) levels in plasma. Sprague-Dawley rats were fed two high fat diets, based on corn (HCO) and extra virgin olive oil (HOO) and results were compared to a low fat diet (LF). LC-MS/MS analysis showed an increasing trend of OEA plasma levels in HOO group, although no significant differences were found. However, body weight gain of LF and HOO were similar and significantly lower than HCO. HCO rats also had higher Lee index than HOO. Rats fed HOO diet showed higher levels of hypothalamic oxt mRNA expression, which could indicate that oxytocin may be modulated by dietary lipids.

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.

Ontogeny of the major xenobiotic-metabolizing enzymes expression and the dietary lipids modulatory effect in the rat dimethylbenz(a)anthracene-induced breast cancer model.

Breast cancer is the most common malignancy in women worldwide. Environmental factors such as xenobiotic exposure and lifestyle and nutrition play a key role in its etiology. This study was designed to evaluate the age-related changes in the expression of major xenobiotic-metabolizing enzymes (XMEs) in the rat liver and the mammary gland in the dimethylbenz(a)anthracene-induced breast cancer model. The influence of dietary lipids on the ontogeny of XMEs was also evaluated. mRNA and protein levels of phase I (CYP1A1, CYP1A2, and CYP1B1) and phase II (NAD(P)H:quinone acceptor oxidoreductase 1 and GSTP1) enzymes were analyzed, as well as their regulation by AhR and Nrf2, respectively. Results showed differences in the phase I enzymes expression, whereas little changes were obtained in phase II. High corn oil and olive oil diets differentially influenced the expression of age-related changes, suggesting that the different susceptibility to xenobiotic exposure depending upon the age may be modulated by dietary factors.

Olive oil and other dietary lipids in breast cancer.

Breast cancer is the most frequent malignant neoplasia among women worldwide. In addition to genetic and endocrine factors, the environment, and specifically nutritional factors, plays a key role in its aetiology. Epidemiological and in particular experimental studies have shown the link between dietary fat and breast cancer. Abundant data have attributed a potentially chemopreventive effect for extra-virgin olive oil (EVOO), the main source of fat in the Mediterranean diet, which is associated with low incidence and mortality rates from chronic diseases such as breast cancer. We have demonstrated the differential modulatory effect of dietary lipids on mammary carcinogenesis, mainly in studies developed in an experimental model. Thus, diets high in n-6 polyunsaturated fatty acids (PUFA) have a clear stimulating influence, whereas EVOO diets mainly have a negative modulatory effect on breast cancer development. The specific mechanisms involved are not fully understood, but nowadays, it is widely accepted that they are numerous and complex. Our group has contributed to improving the knowledge of these mechanisms by demonstrating the influence of dietary lipids on the structure and function of cell membranes, the modulation of cell-signalling transduction pathways, the regulation of gene expression and growth and sexual maturity.

Olive oil, an essential component of the Mediterranean diet, and breast cancer.

OBJECTIVE: The Mediterranean diet has been related to a lower risk of some chronic diseases, including cancer. We aim to gain insight into the effects of the main source of fat of this diet on breast cancer, the most common type of malignancy in women. DESIGN: Data from sixteen experimental series analysing the effects of dietary lipids on mammary carcinogenesis in an animal model, in the context of the international literature on the Mediterranean diet, olive oil and breast cancer risk. SETTING: Experimental and human data on the effects of olive oil and Mediterranean diet on breast cancer. SUBJECTS: An animal model of induced breast cancer and other human and experimental studies in the literature. RESULTS: Diets rich in extra virgin olive oil (EVOO) exert a negative modulatory effect on experimental breast cancer to a weak promoting effect, much lower than that obtained with a high-corn oil diet. EVOO confers to the mammary adenocarcinomas a clinical behaviour and morphological features compatible with low tumour aggressiveness. This differential effect, in relation to other dietary lipids, may be related to a lower effect on body weight and sexual maturation. In addition, EVOO induced different molecular changes in tumours, such as in the composition of cell membranes, activity of signalling proteins and gene expression. All these modifications could induce lower proliferation, higher apoptosis and lower DNA damage. These results, together with the favourable effect of olive oil reported in the literature when it is consumed in moderate quantities, suggest a beneficial influence of EVOO on breast cancer risk. CONCLUSIONS: Consumption of EVOO in moderate quantities and throughout the lifetime appears to be a healthy choice and may favourably influence breast cancer risk.

Modulatory effects and molecular mechanisms of olive oil and other dietary lipids in breast cancer.

Breast cancer is the most common cancer among women worldwide. In addition to genetic and endocrine factors, the environment, and specifically dietary habits, plays a key role in the aetiology of this malignancy. Epidemiological and, especially, experimental studies have shown a relationship between dietary lipids and breast cancer although there are conflicting results concerning their potential to modify cancer risk in humans. Abundant data have attributed a potential chemopreventive effect to extra-virgin olive oil (EVOO), the main source of fat in the Mediterranean diet, which is associated with low incidence and mortality rates from cardiovascular disease and some cancers, including that of the breast. It is well-established that the healthy effects of EVOO can be attributed both to its particular fatty acid composition (a high content in oleic acid (OA), a suitable quantity of essential polyunsaturated fatty acids (PUFA) and a relatively low n-6 PUFA/n-3 PUFA ratio) and its richness in minor bioactive compounds such as squalene and phenolic antioxidants. The specific mechanisms by which EVOO and other dietary lipids may exert their modulatory effects on cancer are not fully understood although abundant research has proposed the following: They influence in the stages of the carcinogenesis process, oxidative stress, alteration of the hormonal status, modification of the structure and function of cell membranes, modulation of cell signalling transduction pathways, regulation of gene expression and influence in the immune system. This article will explore the current knowledge of these mechanisms, including our own results in the context of the international literature.

Diets high in corn oil or extra-virgin olive oil provided from weaning advance sexual maturation and differentially modify susceptibility to mammary carcinogenesis in female rats.

Based on the importance of early-life events in breast cancer risk, we have investigated the effects of high-fat diets on maturation, mammary gland development, and its susceptibility to transformation. Female Sprague-Dawley rats were fed a lowfat (LF), high corn oil (HCO), or high extra-virgin olive oil (HOO) diet from weaning and gavaged with 7,12-dimethylbenz[a]anthracene. Body weight and mass increased in the HCO group compared to the LF group. The vaginal opening was advanced in both high-fat groups, especially in the HCO group. This HCO group also had increased body weight around puberty, more corpora lutea at post-puberty, and tended to have higher kisspeptin levels in the hypothalamus. Both high-fat diets induced subtle modifications in the morphology of the mammary gland, with no changes on ß-casein or hormone receptors expression in the gland. The HCO diet had a clearly stimulating effect of carcinogenesis, inducing the earliest appearance of tumors and the highest tumor incidence and yield, whereas the HOO diet seemed to have a weak enhancing effect, increasing tumor yield. Our data suggest a strong influence of the HCO diet in sexual maturation and mammary cancer risk, while rats fed the HOO diet were more similar to the controls.

High corn oil and extra virgin olive oil diets and experimental mammary carcinogenesis: clinicopathological and immunohistochemical p21Ha-Ras expression study.

Dietary lipids have a role in the aetiology of breast cancer, acting at several cellular levels. We investigated the effects of a high corn oil and a high extra virgin olive oil diet on the clinical and histopathological characteristics of rat dimethylbenz(α)anthracene-induced mammary carcinogenesis and on the expression of p21Ha-Ras, detected by immunohistochemistry, in one experimental series including a low-fat corn oil diet (LFCO) and two high-fat diet groups: HFCO(P), rich in corn oil, and HFOO(P), rich in extra virgin olive oil. Whereas the high corn oil diet tended to reduce latency time, to raise tumour incidence and to increase total tumour yield, the high extra virgin olive oil diet led to a latency time similar to that of LFCO and to a lower tumour incidence than HFCO(P) and lower total tumour yield, even than LFCO. HFCO(P) tumours displayed a higher histological grade and profile than LFCO tumours, while adenocarcinomas in HFOO(P) were similar to LFCO ones. Although no significant differences in p21Ha-Ras expression among dietary groups was found, we detected a significant p21Ha-Ras decreasing expression as grade increased, in groups LFCO and HFCO(P). HFOO(P) tumours exhibited a higher staining in high-grade carcinomas compared to the similar malignant tumours of the two other dietary groups. These data suggest that dietary lipids influence the clinical behaviour and the morphological malignancy of the experimental mammary carcinogenesis, according to the type of fat, without altering p21Ha-Ras expression. Nevertheless, this expression could be affected by the malignancy of tumours, probably through a post-translational event.

Dietary olive oil and corn oil differentially affect experimental breast cancer through distinct modulation of the p21Ras signaling and the proliferation-apoptosis balance.

Extra-virgin olive oil (EVOO) has been hypothesized to have chemopreventive effects on breast cancer, unlike high corn oil (HCO) diets that stimulate it. We have investigated mechanisms of these differential modulatory actions on experimental mammary cancer. In 7,12-dimethylbenz(a)anthracene adenocarcinomas of rats fed a high EVOO, HCO and control diets (n = 20 for each group), we have analyzed the expression and activity of ErbB receptors, p21Ras and its extracellular signal-regulated kinase (ERK) 1/2, Akt and RalA/B effectors by immunoblotting analyses. We explored the Ha-ras1 mutation status by Southern blot, mismatch amplification mutation assay and sequencing, and the 3-hydroxy-3-methylglutaryl-coenzyme A reductase and squalene synthase messenger RNA expression by real-time polymerase chain reaction. We analyzed the tumor mitotic index, proliferating cell nuclear antigen (PCNA) levels, and apoptosis through Caspase-3 analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assays. Finally, we measured the 8-oxo-2'-deoxyguanosine levels. Non-parametrical statistics were used. The EVOO diet decreased Ras activation, downregulated the Ras/phosphatidyl inositol 3-kinase/Akt pathway and upregulated the Raf/Erk pathway, compared with the control. In contrast, the HCO diet did not modify Ras activity but rather enhanced the Raf/Erk pathway. The EVOO diet decreased the cleaved ErbB4 levels, compared with the HCO diet, increased apoptosis and diminished the mono-ubiquitylated PCNA levels, which is related to DNA damage. Tumors from rats fed the EVOO diet displayed a more benign phenotype, whereas those from rats fed the HCO diet were biologically more aggressive. In conclusion, high EVOO and corn oil diets exert their modulatory effects on breast cancer through a different combination of Ras signaling pathways, a different proliferation-apoptosis balance and probably distinct levels of DNA damage.

Differential expression of H19 and vitamin D3 upregulated protein 1 as a mechanism of the modulatory effects of high virgin olive oil and high corn oil diets on experimental mammary tumours.

Dietary lipids have a role in the aetiology of breast cancer. We have reported earlier that a high corn oil diet downregulates H19 and vitamin D3 upregulated protein 1 (VDUP1) messenger RNA (mRNA) expression in rat dimethylbenz (alpha) anthracene-induced mammary adenocarcinomas in comparison with the control low-fat diet, this effect being associated with a higher degree of tumour malignancy. This result was compatible with the stimulating effect of this diet. In this study we have investigated the influence of a high extra virgin olive diet on H19 and VDUP1 mRNA and/or protein expression. We have shown earlier that this high-fat diet confers to the tumours a more benign phenotype in accordance with its potential protective effect on mammary cancer. We have also analysed the effects on the mRNA and protein expression of insulin-like growth factor-2 , in close relation with H19, and the expression and activity of the thioredoxin protein, negatively regulated by VDUP1. mRNA and protein expression were analysed by chemiluminescent northern blot and western blot, respectively. Thioredoxin activity was determined by the insulin-reducing assay. The results showed that the high olive oil diet does not change the tumour expression of H19 and VDUP1. Moreover, tumours from the animals fed this diet displayed higher levels of the insulin-like growth factor-2 mRNAs, which are related to a higher rate of degradation or a lower traducibility. Finally, tumour expression and activity levels of thioredoxin-1 protein did not change irrespective of the diet. These results suggest that the differential effects of high olive oil and high corn oil diets on mammary cancer are exerted by means of a different, specific influence on gene expression.

High corn oil and high extra virgin olive oil diets have different effects on the expression of differentiation-related genes in experimental mammary tumors.

Dietary lipids can modify the clinical behavior and morphological features of experimental breast tumors. We previously demonstrated that a high corn oil diet has a tumor-enhancing effect in 7,12-dimethylbenz(alpha)anthracene (DMBA)-induced rat mammary adenocarcinomas, whereas a high olive oil diet acts as a negative modulator of carcinogenesis. In this study, we investigated whether these high fat diets modulate the expression of genes related to differentiation. Rats were induced with DMBA and fed a low fat diet, a high corn oil diet, a high olive oil diet, or both high fat diets. The expression levels of the mammary differentiation biomarkers alpha-casein, beta-casein and transferrin and of beta-actin and its transporter zipcode binding protein 1 (ZBP1) were analyzed by Northern and/or Western blot in the mammary adenocarcinomas. The high fat diets did not induce changes in the expression of caseins, while transferrin expression was increased as a result of the high olive oil diet. beta-actin mRNA levels were higher in the high fat diet groups, though no changes in the protein levels were observed. The expression of ZBP1, a protein reported as having a role in carcinogenesis, was significantly increased by the high corn oil diet. These results suggest that in this model caseins are not good biomarkers of the changes in tumor morphological differentiation conferred by the high fat diets. The modulation of transferrin and ZBP1 expression by the high olive oil and the high corn oil diets could be one of the mechanisms by which such diets have a different influence on mammary carcinogenesis.

Molecular mechanisms of the effects of olive oil and other dietary lipids on cancer.

Cancer is one of the main causes of mortality worldwide. Geographical differences in incidence rates suggest a key effect of environmental factors, especially diet, in its aetiology. Epidemiologic and experimental studies have found a role of dietary lipids in cancer, particularly breast, colorectal, and prostate cancers. Their incidence in the Mediterranean countries, where the main source of fat is olive oil, is lower than in other areas of the world. Human studies about the effects of dietary lipids are little conclusive, probably due to methodological issues. On the other hand, experimental data have clearly demonstrated that the influence of dietary fats on cancer depends on the quantity and the type of lipids. Whereas a high intake of n-6 PUFA and saturated fat has tumor-enhancing effects, n-3 PUFA, conjugated linoleic acid and gamma-linolenic acid have inhibitory effects. Data regarding MUFA have not always been conclusive, but high olive oil diets seem to have protective effects. Such effects can be due to oleic acid, the main MUFA in olive oil, and to certain minor compounds such as squalene and phenolic compounds. This work aims to review the current knowledge about the relationship between dietary lipids and cancer, with a special emphasis on olive oil, and the molecular mechanisms underlying these effects: modifications on the carcinogenesis stages, hormonal status, cell membrane structure and function, signal transduction pathways, gene expression, and immune system.