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High-fat intake by young Asian women impacts the risk of breast cancer. Understanding the underlying molecular mechanisms may be essential for disease prevention in Asia as well as globally. We aimed to examine the effects of corn oil- and animal fat-based high-fat diets (32.9 and 31.4%, respectively, of fat energy ratio as compared to 12.3% in the standard diet) on mammary carcinogenesis and alterations in gene expression and epigenetic statuses in the mammary gland during the growth stages in a rat model. An increased incidence of carcinomas was observed after the cessation of high-fat feeding. In addition, rapid tumor growth and elevations in Celsr2 expression, which may be a result of DNA hypomethylation patterns in the 3' untranslated region of the gene were noted in the animal fat group. In the human breast carcinoma cell line MCF7, a marginal decrease in cell viability was observed following the knockdown of Celsr2 , suggesting that the animal fat-associated risk of cancer is partly due to the deregulation of mammary cell proliferation via non-metabolic gene functions. The present results will contribute to the development of strategies for controlling the food-associated risk of breast cancer, particularly in younger age groups.

We conducted a meta-analysis to evaluate the association between fat intake and the risk of three major types of skin cancer including basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). A comprehensive search of PubMed and EMBASE was performed to identify all relevant observational studies published up to December 1, 2018. Specific odds ratio (OR) or relative risk (RR) estimates for the highest versus the lowest intake of dietary fat and 95% confidence intervals (CI) from the included studies were pooled using random effect model. Three prospective cohort studies (175,675 participants and 30,915 BCC cases, 4,106 SCC cases and 1,638 CMM cases) and nine case-control studies (328 BCC cases, 493 SCC cases, 1,547 CMM cases and 2,660 controls) were identified. The pooled results indicated that dietary consumption of total fat and saturated fat were not associated with three major types of skin cancer. High consumption of monounsaturated fat was significantly associated with a decreased risk of BCC (RR: 0.90, 95% CI: 0.85-0.96) and high level of polyunsaturated fat intake was potentially positively associated with SCC (RR: 1.19, 95% CI: 1.06-1.33). Our findings should be confirmed by further evidence from well-designed and large-scale prospective cohort studies.

Observational studies have reported controversial evidence of the association between dietary fat intake and ovarian cancer. This dose-response meta-analysis aimed to clarify quantitatively the association between dietary fat intake and ovarian cancer. The linear and non-linear relationships between fat intake and risk of ovarian cancer were investigated. Heterogeneity, sensitivity analysis, and publication bias were also assessed. Overall, 21 studies involved approximately 900,000 subjects were included. A significant nonlinear association was found between total fat intake with the risk of ovarian cancer, with a relatively steep slope at total fat intake higher than 30 g/day ( p non-linearity <.01). Moreover, the risk of ovarian cancer was increased in non-linear form for both saturated and monounsaturated fat from 25 g/day ( p non-linearity <.05). According to the findings from the linear meta-analysis, we observed a 2, 2, 1, and 1% greater risk of ovarian cancer per 10, 0.5, 2.5 g/day and 50 mg/day increase in total, trans and monounsaturated fat intake as well as cholesterol, respectively. However, this association for monounsaturated fat was marginally significant ( p =.052). The findings of this meta-analysis suggest that dietary total, trans, saturated and partially monounsaturated fat as well as cholesterol intake are positively associated with increased risk of ovarian cancer.

Objective: Many studies suggest that high-fat diets are linked to the etiology of non-Hodgkin's lymphoma (NHL). However, the findings are inconsistent and therefore the association between fat and non-Hodgkin's lymphoma remains unclear. In this study, we aim to quantitatively assess the association between fat consumption and the risk for NHL., Methods: We reviewed 221 published cohort and case-control studies that reported relative risk (RRs) and corresponding 95% confidence intervals (CIs) of NHL and fat intake using PubMed, Cochrane, EMBASE, and Google Scholar databases. A random-effects model computed summary risk estimates., Results: Based on our literature search, 10 of 221 studies (two cohort and eight case-control studies) were relevant to this meta-analysis. There was a significant association between total fat consumption and increased risk of NHL (RR = 1.26; 95% CI: 1.12-1.42); in addition, subgroup analysis showed a significant correlation with diffuse large B-cell lymphoma (RR = 1.41; 95% CI: 1.08-1.84) but not with follicular lymphoma (RR = 1.21; 95% CI: 0.97-1.52), small lymphocytic lymphoma/chronic lymphocytic leukemia (RR = 0.91; 95% CI: 0.68-1.23), nor with T cell lymphoma (RR = 1.12; 95% CI: 0.60-2.09). The funnel plot revealed no evidence for publication bias., Conclusion: Total fat consumption, particularly animal fat, increases the risk for NHL.

Nutrition is generally investigated, and findings interpreted, in reference to the activities of individual nutrients. Nutrient composition of foods, food labeling, food fortification, and nutrient recommendations are mostly founded on this assumption, a practice commonly known as reductionism. While such information on specifics is important and occasionally useful in practice, it ignores the coordinated, integrated and virtually symphonic nutrient activity (wholism) that occurs in vivo. With reductionism providing the framework, public confusion abounds and huge monetary and social costs are incurred. Two examples are briefly presented to illustrate, the long time misunderstandings (1) about saturated and total fat as causes of cancer and heart disease and (2) the emergence of the nutrient supplement industry. A new definition of the science of nutrition is urgently needed.

International differences in breast cancer rates and diet, and studies in migrants, suggest that diet may be a modifiable risk factor for breast cancer. The goal of this cross-sectional study was to examine the dietary intakes of women from populations considered to be at different risks for breast cancer. We collected four 24-h food recalls in 3 groups of postmenopausal Canadian women: Caucasians (n = 392), Chinese women born in the West or who migrated to the West before age 21 (n = 156), and recent Chinese migrants (n = 383). Compared to Caucasians, recent Chinese migrants had lower energy and fat intakes and higher protein and carbohydrate intakes. Recent Chinese migrants consumed higher amounts of grains, vegetables, fish, and soy and lower amounts of alcohol, meat, dairy products, and sweets than Caucasians. Western-born Chinese and early Chinese migrants had intakes intermediate between the other 2 groups. The differences in intake between the ethnic groups suggest foods and nutrients that may contribute to the differences in risk of breast cancer between women in Canada and China. Future work will examine whether these dietary differences are associated with biological markers of breast cancer risk.

We examined associations between food intakes and incident breast cancer, defined by estrogen receptor (ER) and progesterone receptor (PR) status in the Malmö Diet and Cancer cohort (∼17,000 women aged 45-73 yr). The hazard ratios (HRs) of ER+PR+ (n = 270), ER+PR- (n = 87), and ER-PR- (n = 61) tumors and all cancer (n = 544) were estimated after 10 yr of follow-up. In multivariate analysis of ER+PR+ tumors, a protective linear risk trend, indicating change between adjoining food categories, was seen with yogurt (HR = 0.89, 95% CI = 0.80-0.99), but increased risks with eggs (HR = 1.10, 95% CI = 1.01-1.20) and dried soups/sauces (HR = 1.10, 95% CI = 1.00-1.22). In ER-PR- tumors, vegetable-oil-based margarine (HR = 1.31, 95% CI = 1.09-1.59) and dried soups/sauces (HR = 1.31 95% CI = 1.05-1.64) showed increased risks. Heterogeneity was observed between ER+PR+ and ER-PR- tumors for vegetable-oil-based margarine (P < 0.01). Regular milk showed decreased, and dried soups/sauces increased, risk with all breast cancer. The study suggests that fat-containing food may contribute both to hormonal and nonhormonal mechanisms in breast tumor development and supports observations of positive associations between characteristics of Westernized diets and postmenopausal breast cancer.

Dietary red meat and animal fat have been linked to endometrial cancer (EC) risk, but the impact of bioavailable iron in animal-derived foods has been less well studied. Our objective was to investigate the effects of iron and fats on the risk of EC in a large, population-based, case-control study. The Shanghai Endometrial Cancer Study enrolled 1,204 EC cases and 1,212 controls who completed in-person interviews, including a food frequency questionnaire. Animal-derived iron and fat intakes were calculated from dietary intakes and food composition tables. Logistic regression models were used to evaluate independent and joint effects of iron and fat on EC risk. Animal-derived iron intake was positively associated with EC risk [adjusted OR = 1.9; 95% CI = 1.4-2.7, P(trend) < 0.01, highest vs. lowest quartile], predominantly after menopause (OR = 2.2; 95%CI = 1.4-3.4, P(trend) < 0.01) and in women with BMI >or= 25 kg/m(2)(OR = 3.2; 95% CI = 1.4-7.5 in postmenopausal obese women, P(trend) < 0.01). Animal-derived fat was also associated with postmenopausal EC risk (OR = 1.7; 95% CI = 1.2-2.5, P(trend) < 0.01). Multiplicative interactions between animal-derived iron and BMI or animal-derived fat intake were not observed. Animal-derived iron intake is associated with increased risk of EC after menopause and among obese women. Avoidance of animal-derived (heme) iron may reduce the risk of EC in these women.

A number of studies exploring associations between individual dietary components and colorectal adenoma or cancer risk have yielded conflicting results. The study of food-based dietary patterns in relation to chronic disease risk represents an alternative approach to the evaluation of single dietary exposures in epidemiological investigations. Results from prospective cohort and population-based case-control studies examining associations between dietary patterns and colorectal cancer or adenoma risk were evaluated and described in this review. Despite notable differences in population characteristics, study design, and methods used for characterizing dietary patterns across the different studies, two general dietary patterns were found to modestly predict colorectal adenoma and cancer risk. A healthier pattern consisting of greater intakes of fruits and vegetables, and lower intakes of red and processed meat, appeared protective against colorectal adenoma and cancer incidence. Findings also suggest that a less healthy pattern characterized by higher intakes of red and processed meat, as well as potatoes and refined carbohydrates, may increase risk. Continued research efforts are needed to evaluate the cumulative and interactive effects of numerous dietary exposures on colorectal cancer risk.

Although mounting evidence suggests that insulin resistance is involved in pancreatic carcinogenesis, few epidemiologic studies have comprehensively investigated the role of lifestyle factors influencing this metabolic disorder in the etiology of pancreatic cancer. We sought to examine this problem in a case-control study conducted in 1994-1998 in Minnesota. Cases (n = 186), aged 20 yr or older, were ascertained from all hospitals in the metropolitan area of the Twin Cities and the Mayo Clinic; from the latter, only cases residing in the Upper Midwest of the United States were recruited. Controls (n = 554) were randomly selected from the general population and frequency matched to cases by age (within 5 yr) and sex. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. After adjustment for confounders, physical activity was associated with a reduced risk, but this protective effect was confined to light activity and moderate activity only (OR = 0.55, 95% CI = 0.30-0.97, P(trend) = 0.038 and OR = 0.51, 95% CI = 0.28-0.93, P(trend) = 0.07, for highest vs. lowest quartile, respectively). An increased risk was found for dietary intakes of energy and fat but was statistically significant for saturated and polyunsaturated fat only. Of note, no appreciable difference in the magnitude of the associations existed between saturated, monounsaturated, and polyunsaturated fat. Compared with individuals in the lowest quartile of fiber intake, the risk was approximately halved for those in the third (OR = 0.49, 95% CI = 0.26-0.94) and the highest quartile (OR = 0.52, 95% CI = 0.21-1.30). Our study lends support to the hypothesis that dietary and other lifestyle factors influencing insulin resistance modulate pancreatic cancer risk.

Processed meat intake may be involved in the etiology of colorectal cancer, a major cause of death in affluent countries. The epidemiologic studies published to date conclude that the excess risk in the highest category of processed meat-eaters is comprised between 20% and 50% compared with non-eaters. In addition, the excess risk per gram of intake is clearly higher than that of fresh red meat. Several hypotheses, which are mainly based on studies carried out on red meat, may explain why processed meat intake is linked to cancer risk. Those that have been tested experimentally are (i) that high-fat diets could promote carcinogenesis via insulin resistance or fecal bile acids; (ii) that cooking meat at a high temperature forms carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons; (iii) that carcinogenic N-nitroso compounds are formed in meat and endogenously; (iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the mucosa, through lipoperoxidation and/or cytotoxicity of fecal water. Nitrosation might increase the toxicity of heme in cured products. Solving this puzzle is a challenge that would permit to reduce cancer load by changing the processes rather than by banning processed meat.

Some dietary compounds, among them fats, are modulators of colon cancer risk. This study reports the modulating effects of n-6, with or without vitamin A, on promotion of colon preneoplasic lesions induced by 1,2-dimethylhydrazine (DMH) and on the expression of nuclear receptors (PPARgamma, RXRalpha, and RARbeta). One group of male Fisher rats was fed a basic diet (5% safflower oil) and two groups were fed a high-fat diet (HFD, 25% safflower oil). Of these, one was supplemented with 200 IU vitamin A for 5 mo. The safflower oil contained polyunsaturated fatty acids, mainly linoleic acid (73%). The data showed an increasing effect of safflower oil-enriched diet on aberrant crypt foci occurrence and multiplicity. This effect was impaired by vitamin A supplementation. In addition, an HFD-related up-regulation of PPARgamma and a concomitant down-regulation of RARbeta mRNA expression were observed with or without chemical initiation and were prevented by vitamin A. Moreover, when treated with DMH, HFD rats exhibited a dramatically decreased expression of RXRalpha mRNA (-49%). It was hypothesized that HFD, leading to hyperexpression of PPARgamma, would produce an alteration of retinoic acid signaling and, in this way, create a background modulating colon cancer risk., (Copyright 2004 Lawrence Erlbaum Associates, Inc.)

The etiology of testicular cancer (TC) remains largely unknown. Few studies have investigated the role diet may play in the etiology of TC. We report on a hospital-based case-control study of TC and selected nutrients and food groups. Cases included 117 patients with primary, incident TC treated at Roswell Park Cancer Institute between 1982 and 1998. A total of 334 hospital controls were frequency matched on age to cases. Cases were categorized by histology (seminoma, nonseminoma, and mixed germ cell TC), and multinomial logistic regression and unconditional logistic regression were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) comparing each histological type with the controls. For nonseminoma and mixed germ cell TC, vitamin E intake was suggestive of reduced risk (OR = 0.51, 95% CI = 0.15-1.76 and OR = 0.36, 95% CI = 0.01-1.31, respectively); for seminoma, it was suggestive of an increased risk (OR = 2.94, 95% CI = 0.99-8.78). Fat intakes were not associated with nonseminoma or mixed germ cell risk; high saturated, animal, and total fat intakes were suggestive of an increase in risk of seminoma. Overall, diet was not associated with TC. However, risk seemed to differ by histology, suggesting that seminoma, nonseminoma, and mixed germ cell TC may have different etiologies. We suggest that future investigations should continue to stratify cases by histology.

Foods associated with precancerous colorectal adenoma, especially those associated with large adenomas, are poorly understood. We compared food intake in polyp-free controls (n = 427) with small adenoma (n = 154) or large adenoma (n = 208) cases in Burgundy (France). Logistic regression models controlled for age, gender, and energy. Consumption of lean meat was associated with a reduced risk of small adenomas [odds ratio (OR) for 4th vs. 1st quartile = 0.3, 95% confidence interval (CI) = 0.2-0.6] and large adenomas (OR = 0.4, 95% CI = 0.3-0.7) compared with controls. There was an increased risk with p t s and meat spread [OR = 2.1, 95% CI = 1.1-3.7 (small adenomas) and OR = 2.6, 95% CI = 1.5-4.4 (large adenomas)], bread [OR = 2.0, 95% CI = 1.1-3.6 (small adenomas) and OR = 2.2, 95% CI = 1.3-3.7 (large adenomas)], and pasta (OR = 1.7, 95% CI = 0.9-3.0 in small adenomas only). Animal fats were associated with an increased risk of large adenomas compared with small adenomas (OR = 2.4, 95% CI = 1.1-5.0), whereas yogurt intake was associated with a lower risk (OR for high vs. no intake = 0.5, 95% CI = 0.3-0.9). These findings suggest that some risk factors that have been found to be associated with cancer, such as refined cereal products and high-fat animal products, also influence early stages of colorectal carcinogenesis.

Trans-fatty acids have been hypothesized to be carcinogenic, although there are limited data in humans testing this hypothesis. In this study, we examine the association between trans-fatty acids and colon cancer using data from a case (n = 1,993)-control (n = 2,410) study conducted in Utah, Northern California, and Minnesota. Dietary data were collected using a detailed diet history questionnaire, and nutrient values were generated from the Nutrition Coordinating Center nutrient database. After adjustment for other variables, including age at diagnosis, body size, physical activity, aspirin and/or nonsteroidal anti-inflammatory drug (referred to collectively as NSAIDs) use, energy intake, and dietary fiber and calcium, we found a weak association in women [odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-2.0] but not in men (OR = 1.2, 95% CI = 0.9-1.7); no increased risk was observed for the cis form of the fatty acids. For men and women, slightly stronger associations were observed in those > or = 67 years of age (OR = 1.4, 95% CI = 0.9-2.1 for men; OR = 1.6, 95% CI = 1.0-2.4 for women). Those who did not use NSAIDs were at a 50% greater risk of developing colon cancer when they consumed high levels of trans-fatty acids. Women who were estrogen negative, i.e., postmenopausal not taking hormone replace therapy, had a twofold increase in risk from high levels of trans-fatty acids in the diet, while women who were estrogen positive did not experience an increased risk of colon cancer, regardless of level of trans-fatty acids consumed. We believe that these data have important public health implications. It seems prudent to avoid consuming partially hydrogenated fats, since no increased risk was observed for the cis form of fatty acids, while suggestions of increased risk from trans-fatty acids exist for subsets of the population.

Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular endothelial cell proliferation, migration, and capillary formation are stimulated by angiogenic growth factors, which include the proteins vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-beta, and eicosanoids synthesized from n-6 fatty acids. Clinical studies have shown that angiogenesis in solid tumors relates to a poor prognosis and, in premalignant lesions, indicates potential for cancerous transformation. High-fat, n-6 fatty acid-rich diets were associated with a relatively poor prognosis in breast cancer patients; in a nude mouse model the same diet enhanced breast cancer progression, whereas n-3 fatty acids exerted suppressive effects that were associated with impaired angiogenesis. Lipoxygenase and cyclooxygenase products of n-6 fatty acid metabolism are angiogenic in in vitro assays. This activity is blocked by pharmacological inhibitors of eicosanoid biosynthesis, and one, indomethacin, suppressed n-6 fatty acid-stimulated murine mammary carcinoma growth and metastasis and tumor vascularization. Review of the experimental data suggests that selective inhibitors of eicosanoid-synthesizing enzymes and dietary intervention with n-3 fatty acids merit clinical evaluation as adjuvant therapy and chemopreventive agents.

Dietary associations were examined as part of a case-control study exploring reasons for exceptionally high rates of lung cancer in northeast Florida. Interviews, which included a nationally standardized food frequency questionnaire, were conducted with 507 patients diagnosed with lung cancer during 1993-1996 or their next of kin and 1,007 persons of similar age, race, and gender randomly selected from the general population. A substantial reduction in risk was associated with high consumption of nutrient-dense fruits and vegetables. Risk was nearly doubled among men and women in the highest quartile of fat intake. The effects were most prominent for saturated and monounsaturated fats and not apparent for polyunsaturated fat consumption. Increased risk was linked to consumption of several individual high-fat foods, including some traditional Southern foods or methods of cooking, such as cooking vegetables with lard/fatback/bacon fat. Reported use of vitamin/mineral supplements was associated with decrease risk of lung cancer as well as dietary consumption of vitamins A, C, and E and some carotenoids. The findings are consistent with emerging evidence that risk of lung cancer rises with increasing dietary fat consumption. They indicate the need for further research to determine whether the association between fat intake and lung cancer is causal and, if so, to clarify the relationships with individual fat fractions.

Our earlier work has shown a selective promotional effect on the genesis of mammary carcinomas bearing a wild-type, but not mutant, Ha-ras codon 12 in a 1-methyl-1-nitrosourea (MNU)-induced carcinogenesis model by high-fat diets (Nutr Cancer 23, 283-290, 1995). To test the hypothesis that activation of the mitogen-activated protein kinase (MAPK) pathway is associated with this promotional effect, we compared the in vivo MAPK phosphorylation state of carcinomas from rats consuming a low-fat (5% corn oil, modified AIN-93G) with that from rats consuming a high-fat (25% corn oil) diet. Specifically, 21-day-old female Sprague-Dawley rats were given an intraperitoneal injection of MNU and one week later were randomized to the two diets for six weeks. The number of mammary carcinomas per rat was 68% greater in the high-fat group, and Ha-ras mutation was rare in this short-term model. The levels of the phosphorylated MAPK2 (active) and of proliferating cell nuclear antigen (PCNA) were significantly higher in carcinomas from the high-fat group, and the two parameters were substantially correlated (r2 = 0.43, p < 0.01). The expression level of c-Raf was fourfold higher in the high-fat group but was only modestly associated with MAPK activation (r2 = 0.35, p < 0.05). The levels of the total MAPK1 and MAPK2, guanosine triphosphatase-activating protein, Ha-Ras, and MAPK kinase did not change. These results suggest that an upregulation of c-Raf expression by high fat may in part account for the in vivo MAPK activation, which in turn may enhance cell proliferation and mammary carcinogenesis.

It is well known that caloric restriction inhibits, whereas excess calories promote, mammary tumorigenesis in rats. However, the relative contribution to carcinogenesis by calories derived from fat or from carbohydrate are not well established. To determine the relative effects of calories from fat or from carbohydrate, as well as any interaction of dietary fiber on the promotion of 7,12-dimethylbenz[a]anthracene-induced mammary tumors, we fed isocalorically nine diets containing different ratios of fat, carbohydrate, and fiber to female Sprague-Dawley rats treated with 7,12-dimethylbenz[a]anthracene (30/group). Under conditions of isocaloric consumption, at or near ad libitum feeding, calories from dietary fat had approximately twofold greater promoting effect on final body weight and tumor incidence than calories derived from dietary carbohydrate. Dietary fiber had an inhibitory effect on tumor development, but the effect was evident only in the high-fat groups. Logistic regression analysis of tumor incidence gave beta-coefficient estimates for the relative effects of fat, carbohydrate, and fiber of 0.866, 0.189, and -4.281, respectively. Time-to-tumor analysis by the Weibull model indicated beta-estimates of 3.016, 3.324, and 5.825 for dietary fat, carbohydrate, and fiber, respectively, indicating that fat shortens and fiber increases the length of time to tumor. The statistical model derived from these results also indicates a significant synergistic interaction of dietary fat and carbohydrate on final body weight and tumor incidence.

The effects of eicosapentaenoic acid [EPA; n-3 polyunsaturated fatty acid (PUFA)], linoleic acid (LA; n-6 PUFA), and palmitic acid (PA; saturated fatty acid) on 1,2-dimethylhydrazine-induced F344 rat colon carcinoma cells (ACL-15) were investigated in vivo and in vitro. The number and size of liver metastatic foci via a superior mesenteric vein injection of ACL-15 cells in F344 rats were significantly inhibited in the EPA-treated group compared with the LA-treated group (p < 0.01); the PA-treated animals and those fed commercial rodent chow (standard diet) demonstrated intermediate values. In a dot immunoblotting assay, vascular cell adhesion molecule 1 expression on ACL-15 cells was downregulated by EPA-ethyl ester treatment and upregulated by LA-ethyl ester treatment compared with the untreated control cells, whereas the expression of matrix metalloproteinase 1 and 2 was not influenced by the fatty acid ethyl esters. In a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, EPA-ethyl ester suppressed ACL-15 cell growth in a schedule-dependent manner, and LA-ethyl ester showed schedule-dependent stimulation. In contrast, PA demonstrated no regulatory effect on cell growth at lower concentrations (< or = 5 mg/ml) but concentration-dependent inhibition at higher concentrations. According to our in vivo cell kinetic study, the difference in tumor growth at the metastatic site was due to different tumor cell proliferation rates; the cell loss rate was not altered. Therefore, the inhibitory effect of liver metastasis on ACL-15 cells by EPA can be explained by a decreased ability of tumor cell adhesion to the capillary bed (low expression of vascular cell adhesion molecule 1) and a lower potential of tumor cell proliferation (low mitotic rate) at the secondary site.

The objective of this study was to investigate the effect of deoxycholic (DCA) and lithocholic (LCA) acids on the postinitiation phases of colon cancer. Male Sprague-Dawley rats (n = 170) were injected with azoxymethane (2 injections at 15 mg/kg body wt sc given 1 wk apart) and fed a control (CON) AIN-93 diet. Two weeks after the second azoxymethane injection, 10 animals were killed and aberrant crypt foci (ACF) were enumerated. The remaining animals were randomly assigned to four diet groups: 1) CON, 2) DCA, 3) LCA, and 4) high fat (HF, a positive control group). Bile acid diets consisted of 0.2% by weight DCA or LCA; HF diets consisted of 20% fat (5% soybean oil + 15% beef tallow by weight). Animals were killed at Weeks 3, 12, and 20 (from 1st carcinogen injection), and number and growth features of ACF and adenomatous lesions were enumerated in the colon. At Week 12, ACF number and small, medium, and large (1-3, 4-6, and > or = 7 crypts/focus, respectively) ACF were higher in the HF group than in the DCA, LCA, and CON groups (p < or = 0.05). By Week 20, ACF number and small, medium, and large ACF were similar in the LCA and HF groups, whereas the response was similar in the DCA and CON groups. Average crypt multiplicity was higher in the HF and LCA groups than in the DCA and CON groups (p < or = 0.05). Microadenoma (MA) incidence was higher in the HF group than in the CON and LCA groups (p < or = 0.05). Regional distribution patterns for ACF number were similar to MA and tumor distribution patterns within the CON, DCA, and HF groups. In the LCA group, ACF number and MA showed a proximal predominance in regional distribution, whereas tumors showed a distal predominance. HF diets provided the most stimulatory environment, immediately enhancing the number and growth of ACF and MA incidence. In conclusion, HF and LCA diets exerted distinct effects on postinitiation phases of colon cancer, whereas the DCA diet did not.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a carcinogenic heterocyclic amine derived from cooked meat. Mammary gland tumors were induced in female Sprague-Dawley rats given 10 doses of PhIP (75 mg/kg po) once per day from 43 days of age and then placed on a defined high-fat (23.5% corn oil) or low-fat (5% corn oil) diet for 25 weeks. Mammary tumor incidence was 49% (44 of 90 rats) and 31% (27 of 88 rats) in the high- and low-fat groups, respectively. No tumors were found in vehicle control rats on the high-or the low-fat diet (n = 44 and 43, respectively). The higher tumor incidence in the high-fat group was due to an increase specifically in carcinomas (classified as tubulopapillary carcinomas) rather than benign tumors (tubular adenomas and fibroadenomas). The incidence of carcinomas was 45% and 24% in PhIP-treated rats on the high- and low-fat diets, respectively. In addition, the percentage of carcinomas showing stromal invasion was highest in the high-fat diet group (22% vs. 8%, high- vs. low-fat diet). Proliferating cell nuclear antigen immunostaining (PCNA) index revealed six times more proliferation in carcinomas from rats on the high-fat diet than in rats on the low-fat diet. Adenomas from rats on different diets had similar PCNA indexes. The tumor apoptotic index, quantitated by immunohistochemical detection (terminal deoxynucleotidyl transferase nick end labeling), was twice as high in carcinomas from rats on the high-fat diet as in carcinomas from rats on the low-fat diet but was similar between the two groups of adenomas. The PCNA-to-apoptosis ratio was 43 and 17 in carcinomas from rats on the high- and low-fat diets, respectively, indicating that the growth rate of carcinomas was greater in rats on the high-fat diet. The results from this study show that the high-fat diet increases the incidence, invasiveness, and growth of PhIP-induced mammary gland carcinomas.

Formulated diets associated with a high risk (HR) or low risk (LR) for colon cancer were used to assess the effect of diet on putative metabolic biomarkers in human flora-associated rats: The HR diet was high in fat and sucrose and low in calcium and fiber; the LR diet was low in fat and high in starch, calcium, and fiber. The nutrient-to-energy ratio and energy intake were the same for both diets. Body and liver weights were significantly higher in animals fed the HR diet, possibly due to greater energy availability from fat. Cecal weights were significantly higher in animals fed the LR diet, presumably due to a bulking effect of the fiber and increased bacterial biomass. The HR diet significantly altered cecal bacterial enzyme activity: beta-glucuronidase activity increased 2.5-fold, and beta-glucosidase activity was halved. Ammonia production and the bacterial metabolism of 2-amino-3-methyl-7H-imidazo[4,5-f] quinoline (IQ) to 7-hydroxy-IQ (7OHIQ) were significantly higher in animals fed the HR diet. The HR diet, which contained factors common to diets consumed throughout the Western world, increased beta-glucuronidase activity, elevated cecal ammonia concentrations, and enhanced the genotoxic risk from 7OHIQ formation, three putative metabolic biomarkers of colorectal cancer. The significance of the reduction in beta-glucosidase is unclear.

In the present study the effects of dietary galactooligosaccharide (GOS) on dietary fat-promoted pancreatic carcinogenesis in azaserine-treated rats were investigated. The aims of this study were to determine 1) whether GOS acts as an inhibitor of pancreatic carcinogenesis and 2) whether GOS interacts with dietary fat-promoted pancreatic tumor development. Four groups of 39 azaserine-treated rats were maintained on different experimental diets that were formulated as follows: 4.3 wt% fat-8.3 wt% GOS (low fat-low GOS), 3.5 wt% fat-27.4 wt% GOS (low fat-high GOS), 15.5 wt% fat-9.5 wt% GOS (high fat-low GOS), and 14.3 wt% fat-28.6 wt% GOS (high fat-high GOS). Autopsies were performed after 6 months (9 animals/group) and 12 months (30 animals/group). Five rats per group were treated with bromodeoxyuridine before autopsy. Parallel sections of the pancreas were stained with hematoxylin and eosin or with hematoxylin and a monoclonal antibody against bromodeoxyuridine and examined by light microscopy. A high-fat diet caused a significant decrease, whereas a diet high in GOS caused a significant increase, in absolute and relative weight of the cecum content. A high level of dietary fat caused a highly significant increase in multiplicity and incidence of pancreatic (pre)neoplastic lesions after 6 and 12 months of feeding. A high level of GOS in the diet did not influence the number of atypical acinar cell nodules or the tumor incidence in comparison with controls. Dietary fat and dietary GOS caused a significant increase in cell proliferation in atypical acinar cell nodules after six months. It was concluded that dietary GOS has no modulating effect on pancreatic carcinogenesis in azaserine-treated rats or on the tumor-promoting effect of a high-fat diet.

The modulation of a vegetables-fruit mixture on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced colorectal carcinogenesis was studied in rats maintained on a low- or a high-fat diet. For this purpose, 120 rats received a semisynthetic diet without (Groups A and C) or with a vegetables-fruit mixture (19.5% wt/wt, Groups B and D) for 35 weeks. Diets of Group A and B contained 20 (low) energy percent (20e%) fat, whereas diets of Groups C and D contained 40e% (high) fat. Between Weeks 4 and 9 the animals were given weekly intrarectal instillations of 6 mg MNNG/kg body wt. The colorectal adenocarcinoma incidences showed a significant decrease in animals fed high-fat diets with a vegetables-fruit mixture compared with animals fed a high-fat diet alone. Furthermore, without a vegetables-fruit mixture, diets high in fat caused a significant increase in adenocarcinoma incidence compared with diets low in fat. Although not significant, the adenoma incidences tended to be lower in animals fed a vegetables-fruit mixture than in animals maintained on a diet without this mixture. The results demonstrate that a vegetables-fruit mixture has a significant inhibitory potency on the development of colorectal tumors induced by MNNG in rats fed diets high in fat.

McKeown-Eyssen and Giovannucci recently proposed that the etiology of insulin resistance (IR) and colorectal cancer (CRC) are related. They suggested that diets high in fat and energy and low in complex carbohydrates and a sedentary life-style lead to IR and that the associated hyperinsulinemia, hypertriglyceridemia, and glycemia lead to increased CRC risk through the growth-promoting effect of insulin or the increased availability of energy. We reasoned that if diet affects colon carcinogenesis through its effect on IR, evidence of colon cancer promotion would be preceded by evidence of IR. To test this expectation, we compared the effects of a high-fat (HF, 59% energy) diet and a low-fat (LF, 11% energy) diet on indirect measures of IR and promotion in azoxymethane-initiated F344 rats. Promotion was assessed as growth of aberrant crypt foci (ACF) at 100 days after initiation. The HF diet increased ACF size 1.4 times (95% confidence interval = 1.30-1.58) that of the LF diet. The HF diet also led to impaired oral glucose tolerance tests measured at 4, 32, 60, and 88 days and characterized by an average increased glucose concentration of 0.78 +/- 0.17 mmol/l (p < 0.001). It also resulted in an impaired intravenous glucose tolerance test and elevated levels of serum insulin after a glucose gavage. We concluded that with this model a high-fat diet leads to evidence of IR before it is possible to demonstrate CRC promotion, thus providing support, necessary but not sufficient, for the causal hypothesis linking IR and CRC. Possible mechanisms linking diet, IR, and promotion are considered.

Previous studies of diet and prostate cancer have focused on advanced disease and have suggested a positive association with saturated fat intake. We report a study assessing the relationship between diet and preclinical prostate cancer. A total of 215 men with preclinical prostate cancer and 593 controls with no evidence of cancer participated in a case-control study conducted in Quebec City between October 1990 and May 1993. The study population comprised two groups: men treated surgically for benign prostatic hypertrophy and participants in a prostate cancer screening program. Trained nutritionists interviewed the participants on their usual diet using a diet history questionnaire. Odds ratios for prostate cancer associated with quartiles of dietary intake and P values for trend were estimated by logistic regression while controlling for age, education, group, and family history of prostate cancer. A positive association was observed between total energy intake and preclinical prostate cancer (p = 0.004). The odds ratios for prostate cancer increased with each quartile of energy intake: 1.00, 1.77, 1.90, and 2.67. After adjustment for energy, nutrients were not associated with prostate cancer. This study provides some evidence that total energy intake is related to preclinical prostate cancer and suggests that diet could be involved earlier than thought in the occurrence of prostate cancer.

The associations between calcium, fat, and cholesterol intake and risk of colorectal cancer were studied in a case-control study conducted in Uruguay. A total of 282 incident and histologically proven cases of adenocarcinomas of the colon and rectum comprised the case series. Five hundred sixty-four hospitalized controls were selected from the same hospitals from which the cases were drawn. Calcium intake was associated with a significant decrease in the risk of colorectal cancer (odds ratio = 0.41, 95% confidence limit = 0.24-0.69 for the uppermost quartile of intake). The associations were similar for colon and rectal cancer. On the other hand, protein and total fat were associated with significantly increased risk of colorectal cancer. A strong interaction between calcium and fat (and cholesterol) intake was found. According to this interaction, calcium effect was maximal at low levels of dietary fat (and cholesterol intake), whereas fat (and cholesterol intake) showed a positive monotonic increase in risk of colorectal cancer at high levels of calcium intake. This finding should be further investigated in other epidemiologic and experimental studies.

Female Sprague-Dawley rats (n = 270) were randomly divided into nine subgroups (30 rats/group) and fed diets with fat contents ranging from 5% to 45% of total energy, in which fat was isocalorically substituted for carbohydrates. At Week 3, the rats were given a single injection of methylnitrosourea (MNU, 50 mg/kg body wt). At Weeks 4 and 5, rats were given an injection of azoxymethane (AOM, 15 mg/kg body wt sc). The rats were maintained on their respective experimental diets until they were sacrificed. Nine weeks after the injection of MNU, 10 rats from each group were killed and their mammary tissue was examined for tumors and their colons for aberrant crypt foci (ACF) formation. The results showed no significant increase in the number of colonic ACF or mammary tumors at 11 weeks among individual groups consuming 5-25% energy from fat or among groups consuming 30-45% energy from fat. Data analysis indicated that the effects of the two diets (5-25% energy from fat and 30-45% energy from fat) on ACF formation as well mammary tumor development were statistically different. Continuation of the diets for 32 weeks led to the development of colonic and mammary tumors. Analysis of the combined group tumor incidence data clearly showed that the colonic and mammary tumor incidence in groups fed 30-45% of energy from fat was significantly higher than that observed among groups fed 5-25% of energy from fat. Linear regression analysis of the colonic ACF at 11 weeks, colonic tumor incidence at 32 weeks, and mammary tumor incidence at 11 and 32 weeks showed good linear correlation, demonstrating the potential value of ACF and mammary tumors at 11 weeks for evaluating the carcinogenic risk associated with different diets. The main conclusion of the experiment is that the incidence of colon and mammary cancers increased rapidly when the dietary levels of fat were increased from 15% to 30% of calories and that there was no significant influence on the colon and mammary cancer risk beyond 30% of calories from fat.

We examined the effect of voluntary physical exercise (running wheels) on pancreatic carcinogenicity of N-nitrosobis-(2-oxopropyl) amine (BOP) in groups of female Syrian hamsters fed a high-fat (HF) diet in which corn oil was 24.6% of the diet or a low-fat (LF) diet in which corn oil was 4.5% of the diet. Each group was divided into an exercising (EX) group (LF-EX and HF-EX) and a sedentary (S) group (LF-S and HF-S). All hamsters were treated with BOP (20 mg/kg body wt) weekly for two weeks beginning four weeks after the experimental diets, which were fed from weaning. A modified glucose tolerance test was performed before the BOP injections and then again at 20 and 40 weeks, and the levels of glucose, insulin-like growth factor I, and insulin were determined in the plasma samples. At the end of the experiment, serum levels of lipid metabolites were also examined in six hamsters from each group. The experiment was terminated 44 weeks after the BOP treatment. Pancreatic ductal/ductular adenocarcinoma incidence was significantly higher in hamsters fed the HF diet (HF-S and HF-EX) than in those fed the LF diet (LF-S and LF-EX). In all groups, glucose and insulin-like growth factor I levels remained within the normal range throughout the experiment, whereas insulin and lipid metabolite levels were significantly elevated in all hamsters fed the HF diet (HF-S and HF-EX). Exercise significantly reduced the insulin level in the group fed the HF diet but did not influence the cancer burden, possibly by the generation of reactive lipid metabolites. Overall, the results showed that voluntary physical exercise does not influence the promotional action of the HF diet on pancreatic carcinogenesis in hamsters. This action could be attributed to the ability of the HF diet to increase the secretion of insulin, which has a growth-promoting and mitogenic effect on pancreatic cells, and to the effect of an HF diet or physical exercise in producing excess free radicals.

Dietary fat intake has been associated with the development of chronic diseases, including heart disease and cancer, in human populations; however, associations demonstrated between disease and fat intake may be confounded by related dietary factors. Therefore, description of the correlates of fat intake in free-living adults may help identify important confounders independent of disease status. In a population of 863 women and 538 men between the ages of 50 and 85 randomly selected from two counties in western New York, we found that most nutrients were correlated with grams of total fat intake including protein, carbohydrates, cholesterol, dietary fiber, retinol, iron, and calcium. Carbohydrates and dietary fiber were not related to the concentration of fat in the diet (% of energy from fat). Alcohol intake was negatively associated with fat concentration for men but not for women. Particularly important for the study of cancers, the antioxidants carotene and ascorbic acid were negatively associated with fat concentration in the diet.

High fat consumption has been implicated as a risk factor for breast cancer. Experimental mammary carcinogenesis studies have demonstrated that the effect of high fat consumption is mainly exerted on the postinitiation stage of the disease process. We report data that have recalled in the formulation of a new hypothesis about the effect of dietary fat on mammary carcinogenesis, namely, that it promotes the development of a subpopulation of cells lacking a specific pathogenetic characteristic. In comparison with animals fed a low-fat diet, female Sprague-Dawley rats fed high-fat diets during the promotional stage developed significantly more (number and proportion) 1-methyl-1-nitrosourea-induced mammary adenocarcinomas that did not contain a codon 12 GGA-->GAA mutation in the c-Ha-ras protooncogene. The effect was independent of the types of fat fed, i.e., corn oil vs. fish oil. A model is presented to account for the preferential promotional effect of high fat consumption on 1-methyl-1-nitrosourea-initiated mammary epithelial cells. The hypothesis that the level of dietary fat consumed affects the proportion of mammary carcinomas that occur with a particular pathogenetic characteristic, in this case, the presence or absence of a Ha-ras point mutation, has important implications on the direction of future investigations concerning fat and cancer risk.

Highly significant correlations exist between total cancer mortality and age expressed by a log total cancer mortality-log age equation (mean r2 0.991 in men and 0.996 in women) or by a second-order polynomial equation including age and age2 (mean r2 0.999 in men and 0.998 in women). In all countries considered (n = 32), the second-order term of age is negative, indicating a decrease in the rate of rise of log cancer mortality at older age. This could be explained by a lesser accuracy of the diagnosis of cancer at older age, by selective survival of subjects resistant to cancer, by a cohort effect, or by a decrease in the rate of growth of cancer at older age. The decrease in the rate of rise of cancer mortality after 65 years of age occurs in all countries and applies to nearly all cancers except breast cancer in women after 75 years of age. A high cancer mortality in a country is characterized by a low intercept and a steep slope of the log mortality-log age equation. These parameters are influenced by dietary fat intake in men and women, with saturated fat increasing total cancer mortality and the ratio of polyunsaturated to saturated fat and the ratio of unsaturated to saturated fat decreasing it. The data on dietary fat were obtained from the Food and Agriculture Organization of the United Nations (FAO) food balance sheets (n = 32) and from dietary surveys (n = 21). Both vary in the same direction, but only the dietary data from the FAO correlate significantly with cancer mortality. This finding points toward a relationship between the level of dietary fat intake and total cancer mortality at the population level.

This review presents the evidence for the hypothesis that dietary linoleic acid and its metabolic derivative arachidonic acid enhance the metastatic process in breast cancer. Key biochemical events are eicosanoid biosynthesis and protein kinase C activation, both of which are involved in tumor cell invasion and angiogenesis. It is concluded that the utilization of appropriate dietary interventions and pharmacological inhibitors offers a promising approach to suppress metastasis.

In a 2.5-year carcinogenicity study, two groups, both including male and female Wistar rats, were fed two different diets with 4% and 16% fat. In addition to 4% soybean oil, the high-fat diet contained 12% mono- and diglycerides, of which 85% was stearic acid and 13% palmitic acid. There was no difference in food consumption, body weight, weight gain, and longevity between the two groups. A statistically significant increase in the incidence of tumors in the high-fat group was seen in fibroadenoma of the mammae (female, p = 0.05). No statistically significant difference was seen when the incidence of benign mammary tumors (adenomas and fibroadenomas) was combined, just as the overall incidence of mammary tumors (adenomas, fibroadenomas, and adenocarcinomas) was not significantly different between the groups. A statistically significant decrease in the incidence of tumors in the high-fat group was seen in adenoma of the parathyroid gland (male, p = 0.04) and medullary carcinoma of the adrenal gland (male, p = 0.04). Combining the incidence of benign and malignant tumors of the adrenal medulla led to a further increase in the level of significance (p = 0.02). The present study showed that a high-fat diet influenced the tumor incidence in certain organs of rats. However, the overall differences in tumor incidence between rats fed the low- and the high-fat diet are considered marginal. Therefore we were not able to confirm or deny the hypothesis that a high-fat diet promotes the development of cancer. It should be noted that, in our study, fat accounted for about 30% of the total energy in the high-fat diet. This is much below the amount of fat normally found in the western diet but corresponds well to the level recommended for human intake. In addition, the rats fed the high-fat diet did not gain more weight, even though no difference was recorded in food consumption (g/kg body wt) between the groups.

The association between self-reported intake of various dietary factors at diagnosis and survival from breast cancer was studied in a population-based cohort of breast cancer patients in Adelaide, South Australia. These patients had been recruited between 1982 and 1984 into a case-control study of diet and incident breast cancer. Of the 451 patients recruited originally, 412 were followed for a median interval of 5.5 years. There were decreases in the risk of death from breast cancer ranging from 25 to 40% at all levels of energy and protein intake above the baseline, whereas for fat intake there was a 40% increase in risk at the uppermost quintile level. There was also some reduction in risk at the upper levels of intake of beta-carotene and vitamin C. However, there were no dose-dependent variations in risk of death by level of intake for any of the dietary factors studied, and most of the variation in risk that was observed was relatively insubstantial.

Amount and type of fat and energy density of diets may influence tumor incidences. The purpose of this report is to summarize the influence of corn oil gavage and different nonpurified diets on spontaneous tumor incidences in 64 diet and 59 corn oil gavage control groups in two-year studies involving approximately 6,100 control Fischer 344 rats of each sex. The maximum mean body weight attained during the course of the study, survival at 106 weeks of age, and spontaneous tumor incidences of groups fed different nonpurified diets with or without corn oil gavage were summarized and evaluated for differences. Male rats fed NIH-07 open-formula diet with or without corn oil gavage had significantly higher body weight, lower survival, and higher incidence of pancreatic acinar cell tumors than rats fed commercial proprietary diets with or without corn oil gavage. Female rats fed NIH-07 diet with or without corn oil gavage had significantly higher body weights and pancreatic tumor incidences than groups fed commercial diets. Time-related trends could account for other apparent differences in tumor incidences between the groups fed commercial and NIH-07 diets. Corn oil gavage significantly increased the body weight and pancreatic tumor incidences but decreased the incidence of leukemia, a lethal tumor, which resulted in higher survival in male rats. Corn oil gavage significantly lowered the body weight and anterior pituitary tumor incidence in female rats. The pancreatic acinar cell tumor incidence appears to be due to a combination of fat intake and body weight.

We present the dietary epidemiology of bladder cancer while controlling for a number of lifestyle and environmental risk factors in a study of 351 white male cases with histologically confirmed transitional cell carcinoma of the bladder and 855 white male controls selected from Erie, Niagara, and Monroe counties of western New York from 1979 to 1985. Usual diet was estimated by comprehensive interviews with use of a detailed food frequency questionnaire. An increased risk of bladder cancer was associated with higher kilocalorie intake, but only among those under 65 years of age, with the strongest pattern associated with fat intake. Further analyses of fat, carbohydrates, and protein, with adjustment for total kilocalories, resulted in a positive association of risk with fat intake and a decreasing risk with higher protein intake. Of the vitamins, carotenoid consumption appeared to decrease risk with increased consumption for those under 65 years of age. No significant differences between cases and controls were seen for intake of calcium, retinol, thiamin, riboflavin, niacin, vitamin C, vitamin D, and vitamin E. After adjustment for kilocalories and other confounders, higher intake of dietary sodium was associated with increased risk among both age groups, and the trends were statistically significant. The importance of diet in the etiology of bladder cancer is suggested by our findings.

This study was performed to evaluate the effect of dietary fat on the recurrence and metastasis of human breast cancer solid tumors growing in nude mice after surgical excision of the primary tumor. Female nude mice were fed either a high- (23% corn oil) or a low-fat (5% corn oil) diet, and 7 days later 1 x 10(6) MDA-MB-435 human breast cancer cells were injected into a thoracic mammary fat pad. Tumors at the injection site grew more rapidly in the animals fed the high-fat diet. Nineteen of 30 animals in each dietary group had tumors with a surface are > or = 1 cm2 within 10 weeks of injection, at which point the tumors were excised and the animals were followed for another eight weeks. Tumors recurred at the excision site in 8 of 19 animals fed the high-fat diet and in 9 of 19 animals fed the low-fat diet; however, the growth rate was more rapid in the group fed the high-fat diet. Lung metastases occurred with similar frequency in the two groups with local recurrences, but with a positive correlation between recurrent tumor weight (greater in the animals fed the high-fat diet) and the severity of lung metastatic involvement. In the mice without recurrence, 4 of 11 (36%) animals in the group fed the high-fat diet had macroscopic lung metastases compared with only one mouse, with minimal involvement, in the group fed the low-fat diet.

We have previously identified dietary patterns among 1,475 male and 780 female normal healthy control subjects in a case-control study of cancer at various sites. In this paper we examine the presence, among persons exhibiting these dietary patterns, of individual health behaviors that may contribute to risks for cancer. Specifically we examine trimming of separable fat from meats, fats used in cooking and as additions to foods, alcohol consumption, and smoking. Results indicate that men and women differ in possession of these high-risk behaviors. Women are more likely to trim fat from meat, consume less alcohol, and have lower exposures to smoking. Their dietary patterns are more independent of the fats used. Several eating patterns are positively associated with total fat intake but differ in their associations with high-risk behaviors. These data suggest that assessing risk associated with dietary patterns sheds more light on disease relationships than studies of single nutrients.

A quantitative overview of 14 studies of rat colon carcinogenesis was undertaken to examine the relationship between fat intake, and fat intake by degree of saturation, on the incidence of colon carcinoma while controlling for calorie consumption. Calorie consumption was not recorded in 11 of the 14 studies. Hence, two types of analyses were conducted. The first examines carcinoma incidence as a function of percent fat (by weight), with calories controlled for by including weight gain per week in the analysis. The second estimates calories per day, for studies not providing such information, using weight gain per week and age at death, followed by a joint analysis of estimated fat calories and estimated total calories. With either approach, a rather strong positive relationship between colon carcinoma incidence and fat intake is indicated for Fischer 344 rats, but no association is apparent for Sprague-Dawley rats. This situation is somewhat clarified when the degree of saturation is taken into account: both strains gave results that suggest a negative relationship between colon cancer incidence and omega-3 fatty acids intake and a positive relationship with non-omega-3 polyunsaturated fat intake among Fischer 344 rats. These analyses suggest an important and specific role for dietary fat in the promotion of rat colon carcinoma.

Growth and development of mammary glandular parenchyma appear to be strongly influenced by the associated adipose tissue. Because fat is the major form of energy storage in the body, any changes in energy balance will be reflected in the weight of adipose tissue to a greater extent than in body weight as a whole. High-fat diets tend to encourage energy storage and may promote mammary cancer by increasing the amount of adipose tissue in the gland. The intimate association of adipose and glandular tissue would facilitate the transfer of any growth-promoting substances, such as polyunsaturated fatty acids, eicosanoids, estrogens, or other growth factors, from the adipose to the glandular tissue. Conversely, low-fat diets or restriction of food intake may decrease the risk of mammary cancer by reducing the amount of adipose tissue and thus reducing exposure of the glandular tissue to such growth-promoting substances.

High-fat, high-cholesterol diets have been linked to colon cancer in both epidemiological and animal studies. Saturated and N-6 polyunsaturated fats have both been implicated as playing causative roles. Epidemiological studies have shown a reduced colon cancer incidence in populations consuming a large quantity of N-3 polyunsaturated fat. This study asked whether N-3 polyunsaturated fat found in fish oil would also be associated with reduced colon cancer in animal studies. 1,2-Dimethylhydrazine was used to induce colon cancer in mice fed three high-fat, high-cholesterol diets (beef tallow, safflower oil, and fish oil) and one low-fat, cholesterol-free diet (soybean oil). Colon adenocarcinomas developed in 55% of mice fed tallow, 48% of those fed low-fat diets, 33% of those fed safflower oil, and 18% of those fed fish oil (p less than 0.05). Tumors per animal were also greatest in mice fed tallow and fewest in those fed fish oil (p less than 0.05). Plasma cholesterol levels were significantly higher in mice fed tallow than in mice fed fish oil, but this did not show any association with tumors. Plasma triglyceride levels were not significantly different among groups but were strongly correlated with colon cancers (r = 0.90, p less than 0.025). In both plasma and colon mucosa cells, saturated fat levels were similar. Monounsaturated fat was highest in plasma of mice fed tallow and correlated strongly with colon cancers (r = 0.84, p less than 0.005). N-6 polyunsaturated fat was highest in plasma and colon mucosa cells of both mice fed safflower oil and those fed low-fat (soybean oil) diet, but there was no association with tumors. N-3 polyunsaturated fat was highest in plasma and colon mucosa cells of mice fed fish oil and showed a negative association with tumors (r = -0.57, p less than 0.05). Thus, in this model of colon cancer, a diet high in fish oil was associated with less colon cancer. Monounsaturated fat was most strongly correlated with tumors. This study suggests monounsaturated fat promotes colon tumors and N-3 polyunsaturated fat inhibits colon tumors.

The relation between dietary cholesterol and fatty acids and the incidence of lung cancer was studied among 4,538 Finnish men aged 20-69 years and initially free of cancer. During 20 years of follow-up, 117 lung cancer cases were diagnosed. Cholesterol intake was not associated with lung cancer risk, the age-, smoking-, and energy-adjusted relative risk between the lowest and highest tertiles being 1.0 [95% confidence interval (CI) = 0.6-1.9]. The intake of saturated fatty acids was nonsignificantly related with lung cancer incidence, the relative risk for the lowest compared with the highest tertile being 1.6 (CI = 0.8-3.2). The association was stronger among smokers than among nonsmokers, the relative risks being 2.1 (CI = 1.0-4.3) and 1.3 (CI = 0.4-4.1), respectively. The relative risk among smokers, however, decreased to 1.5 after adjustment for the amount they smoked. In the total cohort, there was a significantly elevated risk of lung cancer among men with a high intake of butter, one of the main sources of saturated fatty acids, the relative risk being 1.9 (CI = 1.1-3.2). The present data do not confirm previous results suggesting that dietary cholesterol predicts the occurrence of lung cancer among men. The association between intake of saturated fatty acids and lung cancer observed in the present study may be partly due to heavy smoking among high consumers of saturated fat.

Colorectal cancer is the second most common cancer in the United States. Various dietary, colonic, and fecal components have been implicated as causative factors. Although numerous studies have been conducted to test them, so far no one factor has stood out as the most likely cause of colorectal cancer. This review presents the evidence for and against the major factors and concludes that bile acids are the most strongly implicated factors in the etiology of colorectal cancer.

Rats fed diets high (24%) or low (5%) in fat were given dietary levels of vitamin A (retinyl acetate) ranging from 0.3 to 30 micrograms/g food. The lowest tumor incidence was in the group fed diets high in vitamin A and low in fat. When the diet was high in fat and low in vitamin A, tumor incidence and frequency were significantly increased over that in rats fed the high-fat diet with normal levels of vitamin A (10 micrograms/g feed). However, even with a high level of fat in the diet, raising the level of vitamin A above 10 micrograms/g feed had no further beneficial effect. Thus, although there was a significant interaction between vitamin A and fat, it is the latter that appears to require the most attention, once the vitamin A intake is adequate. These data support the view that we should set as a goal an adequate, diversified diet that is low in fat but that an excessive intake of vitamins such as vitamin A that are toxic should be avoided.

The reported milk consumption habits of 3,334 cancer patients and 1,300 comparable control subjects seen at Roswell Park Memorial Institute were studied. The cancer patient group included persons diagnosed with cancers of the oral cavity, stomach, colon, rectum, lung, breast, uterus, cervix, prostate, or bladder. Data were obtained by means of a standardized admissions questionnaire. As a group, control patients were more likely to report never drinking whole milk; cancer patients more often reported frequent consumption of whole milk. Relative risks of different patterns of milk consumption for specific cancer diagnoses, adjusted for sex, age, smoking history, education, and county of residence, were calculated with multiple logistic regression analysis. Elevated risks for frequent consumption of whole milk relative to not drinking milk were observed for cancers of the oral cavity, stomach, colon, rectum, lung, bladder, breast, and cervix. Reduced risks for frequent consumption of 2% milk relative to not drinking milk were observed for cancers of the oral cavity, stomach, rectum, lung, and cervix. Preference for exclusive consumption of reduced-fat milk was linked to significant risk reduction for oral and cervical cancers, and drinking only whole milk was linked to significant risk increases for cancers of the oral cavity, stomach, rectum, lung, and breast. Some associations were observed for a computed index of milk fat intake, but the overall pattern of effects was not fully explained by variations in fat content. The effects observed for some sites may be confounded by other dietary or nondietary correlates of risk.

This article critically reviews the existing, although limited, literature concerning trans fatty acids and tumorigenesis. Neither epidemiological nor experimental studies published to date have demonstrated any valid association between trans fatty acid ingestion and tumorigenesis. A recent study showed that under controlled conditions, a fat with a high content of trans fatty acids did not promote the development of mammary tumors induced in rats by 7,12-dimethylbenz[a]anthracene to any greater extent than did a comparable fat with a high content of cis fatty acids. In addition, in this study a high trans fat was less tumor promoting than was a blend of fats that simulated the dietary fat composition of the United States and had a lower level of trans fatty acids. Another study using comparable cis and trans fats demonstrated that the high trans fat did not affect the growth and metastasis of implanted mammary tumors in mice relative to the high cis fat. Also, two recent studies reported no significant difference in the development of induced colon tumors in rats fed diets high in cis or trans fatty acids. The results of these and other studies are consistent with the conclusion that trans fatty acids are not uniquely related to tumor development.

Diet and nutrition are increasingly recognized as likely to be major determinants of cancer, notably cancers of the gastrointestinal tract, breast, endometrium, ovary, and prostate. Dietary factors may collectively account for a greater proportion of all cancers that occur in contemporary Western society than does any other category of environmental exposure (1). With the development of knowledge of the protective properties of certain components of food, links with diet have been suggested for other cancer sites (2). The epidemiological evidence for the association of diet and cancer is, however, not uniformly convincing; also, the likely biological pathways are not always clear. In this paper, we comment on some current hypotheses in this area and examine the best epidemiological methods to test them.