Search

Proton pump inhibitors (PPIs) have off-target activity on fatty acid synthase (FASN), a critical enzyme in energy balance and cancer growth. We evaluated risk of common obesity-related cancers: breast, colorectal (CRC), and endometrial, with use of PPI and histamine-2 receptor antagonists (H2RA) in 124,931 postmenopausal women enrolled in the Women's Health Initiative. Incident cancer cases were physician-adjudicated. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI) for cancer incidence after year 3. There were 7956 PPI ever users and 9398 H2RA only users. Ever use of either PPI or H2RA was not associated with risk of breast cancer ( n  = 9186) nor risk of endometrial cancer ( n  = 1231). The risk of CRC ( n  = 2280) was significantly lower in PPI users (HR = 0.75, 95% CI = 0.61-0.92), but not in H2RA users (HR = 1.13, 95% CI = 0.97-1.31). The association of PPI use with CRC was apparent regardless of BMI or NSAID use, and was stronger with longer PPI duration ( p  = 0.006) and potency ( p  = 0.005). The findings that PPI use, but not H2RA use, demonstrate an inverse dose-response relationship with risk of CRC is consistent with preclinical data showing FASN inhibition prevents colon cancer progression and supports a role of PPI in CRC prevention.

Herein a Mediterranean Cancer Preventive Diet Score (MCAP Score) is proposed to quantify adherence to both traditional Mediterranean fat intakes and the current dietary recommendations for cancer prevention. The scoring uses research-backed cutoff values, unlike other scores that are based on a population-specific median value. The MCAP score awards positive points for seven preventive food categories, including Mediterranean fats (monounsaturated fats, ω-3 fatty acids) associated with reduced adiposity, and negative points for four food categories associated with increased cancer risk, including ultra-processed foods. In a randomized trial of 120 persons at increased risk of colon cancer, the baseline MCAP Score averaged seven of 20 possible points. Counseling for a Healthy Diet or a Mediterranean Diet improved the score to either 11 or 13 points, respectively, and the highest score observed in any individual was 20 points. The MCAP Score was correlated with serum carotenoids and serum ω-3 fatty acids, and improvements in the score were associated with weight loss over six months of study. The MCAP Score is therefore proposed as a new method to assess adherence to a Mediterranean type of diet for cancer prevention using absolute criteria that will facilitate comparisons of dietary intakes across studies.

This study evaluated changes in fatty acids from sera, red blood cells, and colonic biopsies from a phase Ib clinical trial of personalized ω-3 fatty acid dosing in 47 healthy volunteers. The trial aimed to reduce colonic prostaglandin E 2 (PGE 2 ), a pro-inflammatory product of arachidonic acid (AA) oxidation. The personalized doses ranged 2-10 grams/day (54% eicosapentaenoic acid, EPA, 24% other ω-3 fatty acids). In colon, increases in ω-3 highly unsaturated fatty acids (HUFA) and EPA:AA ratios each were correlated with decreases in PGE 2 . Changes in either colonic EPA:AA ratios or ω-3 HUFA were significantly correlated with changes in the same fatty acid measures in red blood cells or serum. The only blood-based measure significantly correlated with changes in colonic PGE 2 was change in red blood cell ω-3 HUFA (ρ = -0.39), and the increase in red blood cell ω-3 HUFA was significantly greater in participants who had at least a median reduction in colonic PGE 2 vs. those who did not. In summary, fatty acid changes in blood did reflect fatty acid changes in the colon, but additional factors will be needed for optimizing dosing models that seek to predict the anti-inflammatory effects of ω-3 fatty acids on the colon.

Prostaglandin E2 (PGE2) in the colon is a pro-inflammatory mediator that is associated with increased risk of colon cancer. In this study, expression of genes in the PGE2 pathway were quantified in colon biopsies from a trial of a Mediterranean versus a Healthy Eating diet in 113 individuals at high risk for colon cancer. Colon biopsies were obtained before and after 6 months of intervention. Quantitative, real-time PCR was used to measure mRNA expression of prostaglandin H synthases (PTGS1 and 2), prostaglandin E synthases (PTGES1 and 3), prostaglandin dehydrogenase (HPGD), and PGE2 receptors (PTGER2, PTGER4). The most highly expressed genes were HPGD and PTGS1. In multivariate linear regression models of baseline data, both colon saturated fatty acid concentrations and PTGS1 expression were significant, positive predictors of colon PGE2 concentrations after controlling for nonsteroidal anti-inflammatory drug use, gender, age, and smoking status. The effects of dietary intervention on gene expression were minimal with small increases in expression noted for PTGES3 in both arms and in PTGER4 in the Mediterranean arm. These results indicate that short-term dietary change had little effect on enzymes in the prostaglandin pathway in the colon and other factors, such as differences in fatty acid metabolism, might be more influential.

This randomized trial evaluated the effects of intervention with either a Healthy Eating or a Mediterranean diet on colon biomarkers in 120 healthy individuals at increased colon cancer risk. The hypothesis was that eicosanoids and markers of proliferation would be favorably affected by the Mediterranean diet. Colon epithelial biopsy tissues and blood samples were obtained at baseline and after 6 mo of intervention. Colonic eicosanoid concentrations were evaluated by HPLC-MS-MS, and measures of epithelial proliferation and nuclear morphology were evaluated by image analysis of biopsy sections. There was little change in proinflammatory eicosanoids and in plasma cytokine concentrations with either dietary intervention. There was, however, a 50% increase in colonic prostaglandin E3 (PGE3), which is formed from eicosapentanoic acid, in the Mediterranean arm. Unlike PGE2, PGE3, was not significantly affected by regular use of non-steroidal anti-inflammatory drugs at baseline, and normal weight subjects had significantly higher colon PGE3 than overweight or obese subjects. Increased proliferation in the colon at baseline, by Ki67 labeling, was associated with morphological features that defined smaller nuclei in the epithelial cells, lower colon leukotriene concentrations and higher plasma cytokine concentrations. Dietary intervention had little effect on measures of epithelial proliferation or of nuclear morphology. The increase in PGE3 with a Mediterranean diet indicates that in normal colon, diet might affect protective pathways to a greater extent than proinflammatory and proliferative pathways. Hence, biomarkers from cancer models might not be relevant in a true prevention setting.

The available evidence indicates that γ-tocopherol has more potential for colon cancer prevention than α-tocopherol, but little is known about the effects of foods and supplements on tocopherol levels in human colon. This study randomized 120 subjects at increased colon cancer risk to either a Mediterranean or a Healthy Eating diet for 6 mo. Supplement use was reported by 39% of the subjects, and vitamin E intake from supplements was twofold higher than that from foods. Serum α-tocopherol at baseline was positively predicted by dietary intakes of synthetic vitamin E in foods and supplements but not by natural α-tocopherol from foods. For serum γ-tocopherol, dietary γ-tocopherol was not a predictor, but dietary α-tocopherol was a negative predictor. Unlike with serum, the data supported a role for metabolic factors, and not a direct effect of diet, in governing concentrations of both α- and γ-tocopherol in colon. The Mediterranean intervention increased intakes of natural α-tocopherol, which is high in nuts, and decreased intakes of γ-tocopherol, which is low in olive oil. These dietary changes had no significant effects on colon tocopherols. The impact of diet on colon tocopherols therefore appears to be limited.

Smoking and high red meat intake have been associated with colorectal cancer (CRC) risk. Increased iron exposure may be a common factor, favoring the colonization of certain bacterial pathogens that preferentially grow in an iron-rich luminal environment. We analyzed the data from a population-based case-control study of CRC and measured antibody levels against flagelin of Salmonella (FliC), one of the irontrophic bacteria, in 2 independent blood collections. The risk of CRC synergistically increased by combined exposures to heme iron intake and pack-yr (PY) of cigarette smoking (P value for the interaction = 0.039 on the continuous scale). There was a marginally significant interaction between heme iron intake and PY in increasing FliC antibody in the U.S. control subjects (P = 0.055), although no iron or smoking data were available for Dutch samples. Furthermore, FliC antibody levels were significantly higher in patients with colorectal polyps and cancer than in controls in both Dutch (3.93 vs. 2.23) (P = 0.014) and U.S. samples (6.65 vs. 4.37) (P < 0.001). Potential roles of iron from cigarette smoking and dietary heme in CRC through altering irontrophic luminal bacterial population may warrant further investigation.

Quercetin is a flavonol that appears to be protective against several cancers, but its possible role in prevention of colorectal cancer is not yet well studied. We evaluated dietary intakes of quercetin and risk of colorectal cancer in a large case-control study conducted in metropolitan Detroit, Michigan (N = 2664). The protective effects of quercetin intake, as assessed by a food frequency questionnaire, were confined to risk of proximal colon cancer. Stratified analyses showed that the protective effects of quercetin on risk of proximal colon cancer were significant only when fruit intake or the Healthy Eating Index score was high, or when tea intake was low, with odds ratios (OR) for the highest vs. the lowest quartile of 0.49, 0.44, and 0.51, respectively. Increased quercetin intake had no protective effects when tea intake was high. Interestingly, increased intake of quercetin was associated with increased risk of distal colon cancer when total fruit intake was low (OR for the highest vs. the lowest quartile = 1.99). These results suggest that quercetin can have disparate effects on colon cancer risk depending on whether dietary intakes of fruit or tea are high, and that quercetin had protective effects only on proximal, not distal, colon cancer.

The balance of putative pro- and antiinflammatory lipoxygenase (LOX)-derived S-hydroxyeicosatetraenoic acids (S-HETEs) in colon mucosa is a potential target for modulating colon cancer risk and progression. The biological effects of S-HETEs and R-hydroxyeicosatetraenoic acids (produced by distinct pathways) may differ, but levels of these compounds in the colon are unknown. The objective of this study was to develop chiral methods to characterize hydroxyeicosatetraenoic (HETE) enantiomers in colonic mucosa and evaluate the effects of fish oil on HETE formation. C57BL/6 mice (COX-1 null, COX-2 null, wild-type) were fed a diet supplemented with either olive oil or menhaden oil for 11 wk, and R-/S-HETEs in colonic mucosa were quantified by chiral LC-MS/MS. The R-enantiomer comprised 60-72% of 5-HETE, 18-58% of 15-HETE, and 1-16% of 12-HETE in colonic mucosa, suggesting that non-LOX sources contribute to HETE profiles. Fish oil reduced levels of both R- and S-HETEs, and increased the preponderance of the R-enantiomers (particularly 12- and 15-HETEs). There was apparent shunting of arachidonic acid to 12-/15-LOX in the COX-1 null animals. This is the first report of the enantiomeric composition of HETEs in the colon in vivo and shows large effects of fish oil in the normal colon.

This study examined whether subjects who participated in a 12-mo intervention would maintain their diets 1 yr after the study ended and whether the diets of household members were affected. Premenopausal women, who had at least one first-degree relative with breast cancer (n = 122), were randomized to one of four diets: control, low fat (15% of energy), high fruit and vegetable (FV, nine servings per day), and combination low fat, high FV. Study subjects and one household member were asked to complete the Block '95 food-frequency questionnaire (FFQ) at baseline, 1 yr, and 2 yr. Study subjects also completed 24-h recalls and 4-day food records at baseline and Year 1. Fat and FV intakes by all three assessment methods compared reasonably well except that fat intakes by FFQ were somewhat higher. FV intakes by FFQ in the high-FV and combination arms increased significantly from 4 servings per day to about 10 servings per day at Year 1 and 7 servings per day at Year 2. FV intakes increased much more modestly in the low-fat and control arms. Fat intakes in the low-fat and combination arms were lower at Year 1 than Year 2, but mean Year 2 fat intakes of 26-28% were still significantly lower than those at baseline. In household members, the only significant change was a small decrease in energy from fat at Year 1 in the household members of subjects who were in the combination arm. These results indicate that study subjects were making large dietary changes independently of their household members and that fat and FV intakes in study subjects 1 yr after intervention stopped were still substantially different from intakes at baseline.

Dietary patterns that involve both a decrease in fat and an increase in fruit and vegetable (FV) intake may decrease cancer risks. In this study, a total of 122 premenopausal women with a family history of breast cancer were randomized into one of four diets for 12 mo: nonintervention, low-fat (15% of energy from fat), high-FV(9 servings/d), and combination low-fat/high-FV Fasting blood samples were obtained at baseline and after 3, 6, and 12 mo. Levels of 8-isoprostane-F2a in plasma were deter-mined by immunoassay kits. Statistical analyses indicated that levels of 8-isoprostane-F2a decreased significantly with time in the low-fat arm, which is the only intervention that resulted in weight loss; there were no significant changes in the other three diet arms. It is unlikely that this is due to changes in levels of blood lipids because there was little change overtime in plasma total cholesterol, high-density lipoprotein,low-density lipoprotein (LDL), or triglyceride levels in any diet arm, although mean LDL did decrease slightly in women who reduced fat intake after adjustment for change in body mass index (BMI). Levels of baseline 8-isoprostane-F2a were significantly higher in obese women than in overweight or normal weight women, and change in BMI was significantly correlated with change in 8-isoprostane-F2a levels. These results indicate that low-fat diets or high-FV diets are unlikely to affect plasma levels of 8-isoprostane-F2a in healthy,premenopausal women who do not lose weight during dietary change.

Epidemiological studies suggest an inverse association between soy intake and prostate cancer (Pca) risk. We have previously observed that soy isoflavone genistein induces apoptosis and inhibits growth of both androgen-sensitive and androgen-independent Pca cells in vitro. To determine the clinical effects of soy isoflavones on Pca we conducted a pilot study in patients with Pca who had rising serum prostate-specific antigen (PSA) levels. Patients with Pca were enrolled in the study if they had either newly diagnosed and untreated disease under watchful waiting with rising PSA (group I) or had increasing serum PSA following local therapy (group II) or while receiving hormone therapy (group III). The study intervention consisted of 100 mg of soy isoflavone (Novasoy) taken by mouth twice daily for a minimum of 3 or maximum of 6 mo. Forty-one patients were enrolled (4 in group I, 18 in group II, and 19 in group III) and had a median PSA level of 13.3 ng/ml. Thirty-nine patients could be assessed for response. Soy isoflavone supplementation was given for a median of 5.5 (range 0.8-6) mo per patient. Although there were no sustained decreases in PSA qualifying for a complete or partial response, stabilization of the PSA occurred in 83% of patients in hormone-sensitive (group II) and 35% of hormone-refractory (group III) patients. There was a decrease in the rate of the rise of serum PSA in the whole group (P = 0.01) with rates of rise decreasing from 14 to 6% in group II (P = 0.21) and from 31 to 9% in group III (P = 0.05) following the soy isoflavone intervention. Serum genistein and daidzein levels increased during supplementation from 0.11 to 0.65 microM (P = 0.00002) and from 0.11 to 0.51 microM (P = 0.00001), respectively. No significant changes were observed in serum levels of testosterone, IGF-1, IGFBP-3, or 5-OHmdU. These data suggest that soy isoflavones may benefit some patients with Pca.

Dietary patterns that involve a decrease in fat and an increase in fruit and vegetable (FV) intake have been suggested to decrease cancer risks. In this study, intervention methods to selectively modify dietary fat and/or FV intakes were developed. Compliance to the diets and the effects on body weight are shown, because both of these dietary changes can impact on and be confounded by changes in energy intake. A total of 122 women with a family history of breast cancer were randomized onto one of four diets for 12 mo. Counseling methods were devised to increase amount and variety of FV consumed with or without a decrease in fat intake using modified exchange list diets. Women on the low-fat and combination low-fat/high-FV diet arms decreased their fat intakes to approximately 16% of energy. Women on the high-FV and the combination low-fat/high-FV diet arms increased FV intakes to approximately 11 servings/day. Despite counseling efforts to maintain baseline energy intakes, mean body weight increased significantly by 6 pounds in women in the high-FV diet arm and decreased significantly by 5 pounds in women in the low-fat diet arm. Percent body fat also was increased in the high-FV diet arm and decreased in the low-fat diet arm. Body weight and percent body fat in the combination diet arm did not change significantly. Control of energy intake, therefore, appears to have been achieved only when the addition of FV to the diet was balanced by a decrease in fat intake and both dietary components were enumerated daily. Maintenance of energy intake, therefore, did not appear to be attained intrinsically when individuals were counseled to make changes in the composition of their diets.

Dietary fat has previously been shown to have somewhat complicated relationships to levels of oxidative stress in rats. In this study, we examined the effects of five different dietary fat intakes on levels of oxidative DNA damage in rats. Animals fed diets containing 3%, 5%, 10%, or 15% corn oil had body weights that were similar after 20 weeks. Animals fed a 20% fat diet, however, had significantly higher mean body weight than any other group. Levels of 5-hydroxymethyl-2'-deoxyuridine, one marker of oxidative DNA damage, had different relationships to dietary fat in blood and mammary gland. In blood, levels increased with dietary fat levels, and the highest levels were observed with the 20% fat diet (65% higher levels than with the 3% fat diet). In mammary gland, a plateau-type effect was observed, with maximal levels of oxidative DNA damage being obtained using 10% fat (representing a 68% increase relative to the 3% fat diet). This could be a result of induction of compensatory mechanisms in response to a high-fat diet in mammary gland but not in the short-lived nucleated blood cells. Oxidative DNA damage levels in blood thus appear to be a marker of dietary fat intake. In mammary gland, however, levels of DNA damage are consistent with previously observed promotional effects of dietary fat on mammary gland tumorigenesis at lower levels of fat intake with little or no incremental promoting effects at higher levels of fat intake.

The food frequency questionnaire (FFQ) is commonly utilized for assessment of dietary fat intake, but its validity among individuals following a low-fat diet is unclear. We evaluated the agreement of nutrient estimates derived from FFQ, 24-h recall, and 3-day food records obtained from 104 participants in a randomized trial of a low-fat dietary intervention for women at elevated breast cancer risk. Comparisons were made for total calories, percent calories from fat, and total fat after 1 yr. Correlation was assessed using standard methods based on a null hypothesis of no agreement between instruments as well as by a methodology based on a null hypothesis that the instruments should be in agreement. With the use of standard methods, FFQ estimates for women on the low-fat diet were significantly correlated to records only for percent calories from fat (r = 0.39), whereas recall and record estimates were significantly correlated for all three dietary variables. Using the new method, we found no significant correlation between FFQ and either recalls or records for women following a low-fat diet but significant correlation between recall and record estimates for total calories (r = 0.67). Traditional correlation testing may overestimate the extent of agreement in dietary instruments among women on a low-fat diet. We found empirical support for the nontraditional method.

Dietary fat and energy intake have been implicated in breast cancer etiology. To examine the relative importance of these dietary factors on markers of cancer risk in women, we designed an intervention trial to selectively decrease fat and/or energy intake in free-living, premenopausal women who were somewhat overweight. The study used a 2 x 2 factorial design to evaluate the independent and interactive effects of dietary fat and energy. The diets were nonintervention, low fat (15% of energy from fat, maintenance of energy intake), low energy (25% energy reduction), and combination low fat and low energy. We utilized an individualized counseling approach with self-selection of foods. Women on the low-fat and combination diets were asked to meet given daily goals for fat grams and food group exchanges, while women on the low-energy diet used only food group exchanges. Of the 113 premenopausal women randomized who were eligible for analysis, 43% were African-American. A total of 88 women completed the 12-week program, and adherence to the dietary goals was similar in both racial groups. Women on the low-fat diet were able to reduce dietary fat intake to 19% of energy by 4 weeks and to 17% by 12 weeks with a slight decrease in energy intake. Women on the low-energy diet met their energy reduction goals by four weeks while maintaining percentage of energy from fat. Women on the combination diet largely met their goals by four weeks as well. These data indicate that it is possible to selectively manipulate dietary fat and energy intake in women over a short period of time, which makes clinical studies on the relative effects of these two dietary variables on cancer risk biomarkers readily feasible.

Oxidative DNA damage levels may be a marker of breast cancer risk that is modulated by diet. We examined the effects of a high-fat diet fed in varying feeding regimens on levels of 5-hydroxymethyl-2'-deoxyuridine (5-OHmU), an oxidized thymidine residue, in DNA from mammary gland of aging female rats. A total of 48 rats were randomly divided into four groups: ad libitum fed (AL), weight cycled above baseline (WC-G), weight cycled below baseline (WC-L), or energy restricted (ER) for 28 weeks. WC groups were fed repeated ad libitum/restricted amounts of the diet. At sacrifice, both WC groups had body weights similar to the ER group but higher levels of 5-OHmU (p < 0.01). 5-OHmU levels were higher in the WC groups than in the AL group, even though body weights of the WC groups were significantly lower (p < 0.001). These results indicate that a history of weight cycling, even when body weight is reduced, can have adverse effects on 5-OHmU levels in mammary gland DNA, a potential biomarker of cancer risk. Constant control of calories for the maintenance of body weight, therefore, may be more beneficial.