Lipid peroxidation,oxidative stress genes and dietary factors in breast cancer protection: a hypothesis

We have recently proposed that lipid peroxidation may be a common mechanistic pathway by which obesity and hypertension lead to increased renal cell cancer risk. During this exercise, we noted a risk factor swap between breast and kidney cancer (oophorectomy and increased parity, detrimental for kidney, beneficial for breast; high blood pressure, detrimental for kidney, beneficial for breast when it occurs during pregnancy; alcohol, beneficial for kidney, detrimental for breast, and so on). We have subsequently proposed the hypothesis that lipid peroxidation represents a protective mechanism in breast cancer, and reviewed the evidence of the role of lipid peroxidation on established hormonal and non-hormonal factors for breast cancer. Here, we review the evidence in support of lipid peroxidation playing a role in the relationships between dietary factors and breast cancer. Available evidence implicates increased lipid peroxidation products in the anti-carcinogenic effect of suspected protective factors for breast cancer, including soy, marine n-3 fatty acids, green tea, isothiocyanates, and vitamin D and calcium. We also review the epidemiological evidence supporting a modifying effect of oxidative stress genes in dietary factor-breast cancer relationships.     

Understanding meta-analysis in cancer epidemiology: dietary fat and breast cancer

Meta-analyses of the relationship between dietary fat and breast cancer risk using different methodologies have reported conflicting results. This investigation compares methodologic aspects of meta-analyses of patient data (MAP) with meta-analyses of data from the literature (MAL), and computes relative risk (RR) estimates from a random effects model using 28 published studies of dietary fat and breast cancer. MAP and MAL results compare closely when homogeneity is verified. When statistical homogeneity is rejected, a random effects model adjusting for study design and location is appropriate. The highest RR was found for case-control studies of European women (RR: 1.46), followed by North American case-control studies (RR: 1.25), case-control studies of women on other continents (RR: 1.23), cohort studies in Europe (RR: 1.20), and cohort studies in North America (RR: 1.02). The overall risk estimate in a MAL with heterogeneous studies should be interpreted only in a conditional model.     

Colon cancer in Argentina. II: Risk from fibre, fat and nutrients.

A case-control study has been conducted to investigate the relationship between total energy intake, fibre and nutrients and colon cancer in Argentina. Cases are 110 newly diagnosed patients from 10 hospitals between 1985 and 1986. Two neighbourhood controls per case were matched on age, sex and place of residence. The intake of calories, fibre and nutrients was estimated from the information collected on food consumption during the 5-year period up to 6 months prior to interview of subjects, based on a pilot study and standard portion sizes in Argentina. In conditional regression models, dietary fibre is highly protective (odds ratio (OR) = 0.07 per 19.02 g/day; 95% confidence interval (CI): 0.02 to 0.25) and total energy intake increases risk (RR = 1.82 per 1000 kcal/day; 95% CI: 1.20 to 2.77), each with adjustment for the other. Analysis of caloric components (fat, protein and carbohydrates) reveals that carbohydrates are the most important factor driving the total energy effect. Other nutrients make little apparent contribution to risk.     

Association of dietary fat and lung cancer

An international comparison study of the relationship among dietary predictors, tobacco consumption, income, and truncated age-adjusted lung cancer mortality was conducted with the use of time-lagged data available for 43 countries. A regression analysis weighting each country by the square root of the appropriate population and adjusting for several covariates showed that calories from dietary fat were highly significantly associated (P less than .0001) with lung cancer mortality. This finding was obtained after accounting for disappearance data for tobacco (P less than .0001), the dominant risk factor for lung cancer, and total nonfat calories (P less than .002). Other covariates included per capita gross national product and proportion of calories from fruits, vegetables, roots, tubers, and pulses. Weaknesses of this study, statistical considerations, biologic plausibility, in particular the modulation of tobacco-smoke carcinogens by lipids in the lung, and suggestions for future study are discussed.     

Role of fat, animal protein, and dietary fiber in breast cancer etiology: a case-control study

A case-control study of 818 breast cancer (BC) patients and 2 matched control groups, surgical controls (SCs) and neighborhood controls (NCs), was undertaken in Israel between 1975 and 1978. The interview schedule included a detailed dietary history based on the frequency of consumption of 250 food items, which were grouped according to their principal nutrient component. The average frequency of consumption of each food item in each nutrient group was computed. Medical, demographic, hormonal, and parity histories were also obtained. Risks associated with fat, animal protein, and fiber consumption were evaluated. Two types of analysis were performed [in 2 age groups (less than 50 yr and greater than or equal to 50 yr)], using the conditional logistic method: evaluating the risk attributable to nutrition only and controlling for nondietary confounding factors as well. When no adjustment for nondietary confounding factors was made, the risk increased with fat intake in both age groups [one-tailed P-value for linear trend = .08 and .07 in age less than 50 and .01 and .10 for the greater than or equal to 50 age category for the BC case (BCC)-SC and BCC-NC comparisons, respectively]. Increased fiber intake decreased the risk in the younger age group (one-tailed P-value for linear trend = .06 and .07 for the BCC-SC and BCC-NC comparisons, respectively), while in the 50-or-over age category the trend was inconsistent. The risk associated with animal protein was much less clear. For women in the highest quartiles of fat and animal protein intake and the lowest quartiles of fiber intake, risk was about twice as high as that for women in the lowest quartiles of fat and animal protein intake and in the highest quartile of fiber intake (one-tailed P-value for linear trend = .04 and .08 for age less than 50 and .08 and .09 for the age category greater than or equal to 50 BCC-SC and BCC-NC comparisons, respectively). When hormonal and demographic confounding factors were controlled for, this pattern persisted but it remained significant for 1 control only. Power increased when cases were analyzed against both controls simultaneously (one-tailed P-value for linear trend = .10 for age less than 50 and .02 for age greater than or equal to 50). Thus a higher fat-animal protein and lower fiber diet is associated with increased cancer risk, but this relationship needs to be studied further.     

Adult dietary fat intake and ovarian cancer risk

The association of dietary fat intake with ovarian cancer risk has been inconsistent across populations. We examined dietary fat intake, overall and by type and ovarian cancer risk in two prospective cohort studies. We assessed long-term dietary fat intake among Nurses’ Health Study (NHS) and NHSII participants using food frequency questionnaires administered every 2–4 years beginning in 1984 and 1991, respectively. We examined cumulative energy-adjusted intake of total fat, specific types of fat (animal, vegetable, saturated, monounsaturated, polyunsaturated and trans fat) and cholesterol. We identified 700 ovarian cancer cases in NHS and 196 in NHSII with dietary information. Cox proportional hazards regression was used to estimate associations between intake and ovarian cancer risk. Dietary fat intake changed over time in both cohorts and was lower in NHS than NHSII. Higher cumulative average intakes of animal fat and cholesterol were significantly positively associated with risk of ovarian cancer in NHS (relative risk [RR] comparing extreme quartiles = 1.57, 95% CI: 1.20, 2.06 and 1.35, 95% CI: 1.08, 1.69, respectively), but not in NHSII. Other dietary fat sources were not clearly associated with risk in either population. We did not observe clear associations between dietary fat and ovarian cancer risk in two large prospective cohort studies.     

Types of dietary fat and breast cancer: a pooled analysis of cohort studies

Recently, there has been interest in whether intakes of specific types of fat are associated with breast cancer risk independently of other types of fat, but results have been inconsistent. We identified 8 prospective studies that met predefined criteria and analyzed their primary data using a standardized approach. Holding total energy intake constant, we calculated relative risks for increments of 5% of energy for each type of fat compared with an equivalent amount of energy from carbohydrates or from other types of fat. We combined study-specific relative risks using a random effects model. In the pooled database, 7,329 incident invasive breast cancer cases occurred among 351,821 women. The pooled relative risks (95% confidence intervals [CI]) for an increment of 5% of energy were 1.09 (1.00-1.19) for saturated, 0.93 (0.84-1.03) for monounsaturated and 1.05 (0.96-1.16) for polyunsaturated fat compared with equivalent energy intake from carbohydrates. For a 5% of energy increment, the relative risks were 1.18 (95% CI 0.99-1.42) for substituting saturated for monounsaturated fat, 0.98 (95% CI 0.85-1.12) for substituting saturated for polyunsaturated fat and 0.87 (95% CI 0.73-1.02) for substituting monounsaturated for polyunsaturated fat. No associations were observed for animal or vegetable fat intakes. These associations were not modified by menopausal status. These data are suggestive of only a weak positive association with substitution of saturated fat for carbohydrate consumption; none of the other types of fat examined was significantly associated with breast cancer risk relative to an equivalent reduction in carbohydrate consumption.     

Meta-analysis: dietary fat intake, serum estrogen levels, and the risk of breast cancer

BACKGROUND: There is compelling evidence that estrogens influence breast cancer risk. Since the mid-1980s, dietary fat intervention studies have been conducted to investigate the effect of fat intake on endogenous estrogen levels. To further our understanding of the possible relationship between dietary fat and breast cancer, we conducted a meta-analysis of dietary fat intervention studies that investigated serum estradiol levels, and we reviewed the nature of the evidence provided by prospective analytic studies of fat consumption and breast cancer risk. METHODS: A computerized search of the English language literature on estrogen/estradiol and dietary fat intervention studies published from January 1966 through June 1998 was conducted using the MEDLINE database. Pooled estimates were derived from the change in estradiol levels associated with fat reduction from 13 studies. Analyses were conducted separately for premenopausal and postmenopausal women and in both groups combined. RESULTS AND CONCLUSIONS: Statistically significant reductions in serum estradiol levels of -7.4% (95% confidence interval [CI] = -11.7% to -2.9%) among premenopausal women and -23.0% (95% CI = -27.7% to -18.1%) among postmenopausal women were observed, with an overall -13.4% (95% CI = -16.6% to -10.1%) reduction observed. The greatest reductions occurred in two studies in which dietary fat was reduced to 10%-12% of calories compared with 18%-25% of calories in the other studies. A statistically significant reduction in estradiol levels of -6.6% (95% CI = -10.3% to -2.7%) remained after exclusion of these two studies. Review of prospective analytic epidemiologic studies that allowed for dietary measurement error suggests that the possibility that reducing fat consumption below 20% of calories will reduce breast cancer risk cannot be excluded. Implications: Dietary fat reduction can result in a lowering of serum estradiol levels and such dietary modification may still offer an approach to breast cancer prevention.     

Vitamin D receptor start codon polymorphism and colorectal cancer risk: effect modification by dietary calcium and fat in Singapore Chinese

Vitamin D has been implicated as a protective agent against colorectal cancer. We hypothesized that a functional start codon polymorphism in the vitamin D receptor (VDR) influences the risk of colorectal carcinoma. We conducted a case-control study nested within a large cohort of Singapore Chinese. VDR genotypes, determined by FokI restriction endonuclease digestion of PCR-amplified DNA, were performed on 217 colorectal cancer cases and 890 controls. We found that compared with individuals carrying the FF genotype, those with Ff genotype had a 51% increase in risk of colorectal cancer and those with the ff genotype, an 84% increase in risk (P for trend = 0.01). The effect of the VDR genotype on risk appeared to be modified by both dietary calcium and fat. Among those with either low calcium or low fat intake (below the median values in controls), the risk for colorectal cancer increased in a gene-dose-dependent manner such that individuals possessing the ff genotype displayed an approximately 2.5-fold increased risk that was statistically significant. There was little evidence of a VDR genotype-colorectal cancer association among subjects with higher than median values of either dietary fat or calcium.     

Colon cancer in rapidly developing countries: review of the lifestyle, dietary, consanguinity and hereditary risk factors

Colon cancer rates are rising dramatically in once low incidence nations. These nations are undergoing rapid economic development and are known as “nations in transition” (NIT). This review identifies some of the most common etiological risk factors of colon cancer in these nations and evaluates the existing epidemiological evidence. The main risk factors which were found to be prevalent in NIT include: lifestyle factors such as physical inactivity, obesity and abdominal adiposity, alcohol consumption and cigarette smoking; dietary factors such as fatty food and red meat consumption. Protective factors included white meat and fiber consumption. Several studies found to have significantly higher rates of colon cancer among the young population (<40 years old). There appears to be a quantitative and qualitative increase in risk to relatives of patients diagnosed at a young age compared with those diagnosed later in life, at least part of which is likely to be the result of a hereditary susceptibility. Close relatives of patients with colon cancer are at an increased risk of developing a colon cancer. Close relatives of early onset cases warrant more intensive endoscopic screening and at an earlier age than relatives of patients diagnosed at older ages. Furthermore, these suggest the existence of genetic predispositions in these nations which need to be investigated further and have implications for screening programs. In conclusion, public health awareness campaigns promoting prevention of modifiable risk factors and screening initiatives with guidelines suited to the age-specific incidence rates of NIT are needed very urgently.     

Pancreatic cancer,animal protein and dietary fat in a population-based study,San Francisco Bay Area,California

Objective The associations between animal protein or fat and risk of pancreatic cancer have been reported previously with inconsistent results. A population-based case–control study of pancreatic cancer was conducted in the San Francisco Bay Area to examine these associations. Methods A semi-quantitative food-frequency questionnaire was administered to 532 cases and 1,701 controls between 1995 and 1999. Odds ratios (OR) and 95% confidence intervals (CI) were computed as estimates of the relative risk of pancreatic cancer. Results When comparing highest versus lowest levels of intake in multivariable adjusted models, positive associations were observed for several beef/lamb and individual animal protein items, including beef/lamb as a main dish (OR = 2.2, 95% CI: 1.0–4.5), regular hamburger (OR = 1.7, 95% CI: 1.2–2.4), whole eggs (OR = 1.6, 95% CI: 1.0–2.4), butter (OR = 2.4, 95% CI: 1.6–3.5), and total dairy not including butter (OR = 2.6, 95% CI: 1.8–3.7). Some high-fat/processed-meat products (i.e., sausage, salami, bacon), but not all (i.e., beef, pork, or poultry hot dogs), also were positively associated with risk. An inverse association was noted for greater chicken/turkey consumption (OR = 0.7, 95% CI: 0.5–1.0). The risk comparing the highest versus lowest quartiles for fats and cholesterol consumption were: total fat (OR = 1.6, 95% CI: 1.2–2.1); animal fat (OR = 1.9, 95% CI: 1.4–2.5); saturated fat (OR = 1.9, 95% CI: 1.4–2.6); monounsaturated fat (OR = 1.3, 95% CI: 1.0–1.8); and dietary cholesterol (OR = 1.5, 95% CI: 1.1–2.0, all p-trends ≤ 0.02). Conclusions These data provide some evidence that beef or lamb, eggs, dairy, fat, or cholesterol may increase the risk of pancreatic cancer.     

Proliferative activity of murine mammary epithelium as affected by dietary fat and calcium

Dietary fat and calcium have been found to affect significantly the proliferative status of the mammary glands. Female mice (3-week-old C57BL/6J) were given either a low or high corn oil diet (3 or 30% by weight). One, 2, or 4 weeks after the dietary intervention the animals were given injections of [3H]thymidine and/or colchicine; 2 h later their thoracic mammary glands were removed and processed for histology and autoradiography. Animals on the high corn oil diet had an increased labeling index of both terminal ducts and mature ducts compared to the control group at each time (i.e., 10.1 +/- 2.1 versus 4.8 +/- 0.9% at 2 weeks). This effect of a high corn oil diet was evident on the mammary glands of animals at various ages. Animals on a high beef tallow diet also had a high labeling index. This effect of a high fat diet appeared to be reduced by dietary calcium. The labeling index for terminal ducts of animals on high corn oil diet decreased from 14.1 +/- 3.8, 11.9 +/- 3.4 to 8.5 +/- 1.8 and high beef tallow from 13.6 +/- 3.6, 11.4 +/- 0.7 to 9.5 +/- 1.3 for calcium levels of 0.1, 0.5, and 1.0%, respectively. Mitotic indices followed the same trend. These studies demonstrate that a high fat diet affects the proliferative status in the mouse mammary glands in a short period of time and that this effect can be reduced by dietary calcium.     

Adolescent dietary fiber,vegetable fat,vegetable protein,and nut intakes and breast cancer risk

The importance of early-life exposures in breast cancer development is increasingly recognized. However, limited research has evaluated the relationship between adolescent diet and subsequent risk of breast cancer and reported inconsistent results. This population-based case–control study investigated the associations of dietary fiber, vegetable protein, vegetable fat, and nuts consumed during adolescence with adult breast cancer risk. Women, ages 25–74 years, who were diagnosed with first primary breast cancer between 2002 and 2003, were identified using the Ontario Cancer Registry. Controls were identified through random-digit dialing and age-frequency matched to cases. Diet at ages 10–15 was assessed with a 55-item food frequency questionnaire among 2,865 cases and 3,299 controls. Logistic regression was performed to estimate odds ratios (ORs) and 95 % confidence intervals (CIs). Inverse associations were found between intakes of dietary fiber, vegetable protein, vegetable fat, and nuts during adolescence and breast cancer risk, which persisted after controlling for adult intakes. The ORs (95 % CI) for the highest versus the lowest quintile of intake were 0.66 (0.55–0.78; P _trend < 0.0001) for fiber, 0.80 (0.68–0.95; P _trend = 0.01) for vegetable protein, 0.74 (0.63–0.87; P _trend = 0.002) for vegetable fat, and 0.76 (0.61–0.95 for ≥1 serving/day vs. <1 serving/month intake; P _trend = 0.04) for nuts. The reduced risk for adolescent intakes of fiber, vegetable protein, and nuts was largely limited to postmenopausal women (P _interaction ≤ 0.05). Dietary fiber, vegetable protein, vegetable fat, and nuts consumed during adolescence were associated with reduced breast cancer risk.     

Colon cancer in Argentina. I: Risk from intake of dietary items.

A case-control study has been conducted to investigate the relationship between dietary components and risk of colon cancer in the La Plata area of Argentina. Cases are 110 patients newly diagnosed with colon cancer in 10 major hospitals between 1985 and 1986. Two neighbourhood controls per case were individually matched by age, sex and place of residence. Personal interviews elicited information on frequency of consumption of 140 food items during the 5-year period up to 6 months prior to interview. Risk is analyzed by quartiles of individual food items and groups of items. Multivariate conditional logistic regression modelling indicates that consumption of eggs is associated with increased risk for colon cancer (odds ratios by quartile: 1.0, 1.58, 2.02, 4.66), as are some dairy products (ORs of 1.93 for the highest quartile of consumption of cheese). Intake of vegetables, fish and poultry is associated with statistically significant decreasing risk (ORs of 0.075, 0.39 and 0.39, for the highest categories of consumption of vegetables, fish and poultry, respectively). The risk for red meat does not consistently increase as consumption increases. Risks are not altered by the inclusion of potential confounders such as education or body mass index. These findings confirm those of several previous studies and are of particular interest, since the Argentinean diet typically includes a high intake of red meat.     

Inflammation and endometrial cancer: a hypothesis.

Endometrial cancer is the most common gynecologic malignancy in the United States. Substantial epidemiologic data implicate an imbalance of estrogens and progestogens in the etiology of this disease. We propose that inflammation also plays a role in endometrial cancer development. Emerging laboratory data suggest that elevated levels of prostaglandin E(2) may underlie the transformation of normal endometrium to neoplastic tissue and that in vitro nonsteroidal anti-inflammatory drugs may inhibit endometrial cancer cell growth. In this review, we suggest that the risk factors for endometrial cancer--unopposed estrogens, anovulation, polycystic ovary syndrome, excessive menstruation, early menarche, and late menopause--may be viewed as factors increasing the exposure of the endometrium to inflammation, whereas pregnancy and smoking, two likely protective factors, have the opposite effect. Chronic inflammation can induce rapid cell division, increasing the possibility for replication error, ineffective DNA repair, and subsequent mutations. A proinflammatory milieu can also directly increase estrogen production. Hence, inflammation may work in conjunction with or in addition to estrogen exposure in the development of endometrial cancer.