Relationship Between Meat Intake and Breast Cancer Risks

Relationship Between Meat Intake and Breast Cancer Risks COOKED MEAT INTAKE AND THE RISK OF BREAST CANCER M. MOGA*, I. MANITIU, N. BIGIU Abstract. Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) are carcinogens formed in or on the surface of well-done meat, cooked at high temperature. The aim of this analysis was to assess the risk of breast cancer related to the intake of cooked meat. The data support the accumulating evidence that consumption of meats cooked by methods that promote carcinogen formation may increase risk of breast cancer. Keywords', breast cancer, cooked meat, polycyclic aromatic hydrocarbons, heterocyclic amines, carcinogens. AIMS AND BACKGROUND Breast cancer is the leading cause of cancer death among women in developed countries. Foods and food groups that have individually shown potentially important associations with breast cancer risk include alcohol, fruit and vegetables, fat, red meat, sugar, low-fat dairy products, fish, and tea. Red meat intake has been hypothesised to increase breast cancer risk. Both case-control1 and ecologic2 studies have supported a positive association, and an expert panel described red meat intake as a possible cause of breast cancer3. Cumulative evidence suggests a possible interaction of cooking methods with diet in the pathogenesis of breast cancer. Meats cooked to well-done at high temperatures contain heterocyclic amines (HCAs), such as 2-amino-3,4,8-trimethylimidazo[4,5-/]quinoxaline (DiMelQx). 2-amino-3,8-dimethylimidazo[4,5-/]qumoxaline(MeIQx), and2-amino-l-methyl- 6-phenylimidazo[4,5-6]pyridine (PhIP) (Ref. 4). The amounts of these compounds vary according to cooking technique, temperature, cooking time, and type of meat5. Experimental evidence over more than two decades has led to the proposal that heterocyclic aromatic amines (HAAs) may be causal factors in human breast cancer. HAAs are formed as a result of cooking meat for long durations by common high temperature methods such as barbecuing, grilling and pan frying. Mammary carcinogenesis has been demonstrated as a 'cell proliferation'mode! in which hormones, such as estrogens, both induce and promote mammary tumors ' For correspondence. increasing mammary cell division6. It is plausible that cells during division are re susceptible to carcinogenic stimulus, or hormones trigger the progression of rumor cells initiated by carcinogens. After menopause, adipose tissue is the r site for estrogen synthesis, and women with a high body mass index (BMI) e an elevated level of endogenous estrogens7. Therefore, it is possible that (estrogens and estrogen-related factors, such as BMI, may modify the association kxween intake of carcinogens from foods cooked at high temperature and breast ceicer risk. Adolescence may be a period of increased susceptibility to breast cancer due x regular division of undifferentiated cells that occurs between puberty and first tarth. Red meat consumption during early adult life has been associated with breast ^ncer risk. EXPERIMENTAL Experimental evidence over more than two decades has led to the proposal that ie:erocyclic aromatic amines (HAAs) may be causal factors in human breast can- csr. HAAs are formed as a result of cooking meat for long durations by common temperature methods such as barbecuing, grilling and pan frying. Several epidemiological studies have revealed an increasedrisk of breast cancer associated ~ high meat intake8-11. Evidence from some recent epidemiological studies has suggested that intake ;: well-done meat and concomitant mammary carcinogens may be associated with i substantially elevated risk of breast cancer9-12. Similar to grilling and pan-frying, deep-frying, although rarely studied previ- : usly, is a high temperature (typically 240-270 °C) cooking method and may also result in the production of many chemicals, including heterocyclic amines and polycyclic aromatic hydrocarbons13. In addition to volatile mutagenic compounds, nonvolatile detrimental products, such as hydroperoxides, trans fatty acids, and aldehydes can be detected in deep-fried soybean oil. Deep-frying cooking is one : f the most common cooking methods in China and many other countries. Q. Dai, X. Shu14 evaluated the association of animal food intake and degree of browning by deep-frying with breast cancer risk in a population-based case- :ontrol study conducted during 1996-1998 among Chinese women in Shanghai, a population with a traditionally low risk of breast cancer. The study suggests that high intake of deep-fried, well-done red meat may be associated with an increased risk of breast cancer, and the positive association may be modifiedby body weight. The same study also suggests that nonhydrogenated soybean oil, if not used in high- temperature cooking, may be associated with a reduced risk of breast cancer. The preponderance of evidence from animal and human studies has substantiated a causal relationship between postmenopausal estrogen levels and the risk of breast cancer15-17. Mammary carcinogenesis has been demonstrated as a 'cell proliferation'model in which hormones, such as estrogens, both induce and promote mammary tumors by increasing mammary cell division6. It is plausible that cells during division are more susceptible to carcinogenic stimulus, or hormones trigger the progression of the tumor cells initiated by carcinogens. After menopause, adipose tissue is the major site for estrogen synthesis, and women with a high BMI have an elevated level of endogenous estrogens7. Therefore, it is possible that estrogens and estrogen-related factors, such as BMI, may modify the association between intake of carcinogens from foods cooked at high temperature and breast cancer risk. One previous case-control study conducted in Uruguay found a stronger positive association of breast cancer risk with fried meat than with broiled meat9. Oil temperature is normally at approximately 240-270 °C when used for deep-fried cooking. It has been reported that deep-fried cooking oil not only produces fumes containing mutagenic compounds, such as 1,3-butadiene, benzene, acrolein, and formaldehyde18, but also generates nonvolatile hazardous compounds, such as hydroperoxides, trans fatty acids, and aldehydes19. Both hydroperoxides and aldehydes are endogenous reactive chemicals and have mutagenic and carcinogenic potential20. Other factors related to insulin resistance, such as high insulin, C-peptide, and insulin-like growth factor-1, and low physical activity have also Ijeen shown to be associated with an increased risk of breast cancer in several studies21-23. It is plausible that high levels of insulin and estrogens may stimulate the transformation of breast cancer cells initiated by carcinogens from well-done meats and heated cooking oils23 and, therefore, promote the development of breast cancer. Several recent epidemiological studies have suggested that trans fatty acids may be a risk factor for breast cancer24. Steck and Gaudet25 estimated breast cancer risk in relation to intake of cooked meat in a population-based, case-control study (1508 cases and 1556 controls) conducted in Long Island, NY from 1996 to 1997. Modest increased risk was observed among postmenopausal women consuming the most grilled or barbecued and smoked meats over the life course (OR = 1.47; CI = 1.12-1.92 for highest versus lowest fertile of intake). Postmenopausal women with low fruit and vegetable intake, but high lifetime intake of grilled or barbecued and smoked meats, had a higher OR of 1.74 (CI = 1.20-2.50) and the results support the accumulating evidence that consumption of meats cooked by methods that promote carcinogen formation may increase risk of postmenopausal breast cance25. Rohrmann26 conducted a study to examine the association of the consumption of meat in general, meat prepared by different cooking methods and the dietary intake of heterocyclic aromatic amines (HCA) with the level of DNA adducts in  ±e breast tissue of women undergoing reduction mammoplasty. They observed strong correlations of dietary HCA intake and consumption of fried and processed neat with DNA adduct levels in breast tissue of 44 women. De Stefani and Ronco27 studied the effects of meat intake, including heterocyclic amine exposure, on the risk of breast cancer. They conducted a hospital-based case-control study involving 352 patients with breast cancer and 382 controls. A strong effect of red meat, total meat, beef, fried meat, and heterocyclic amine exposure was found, after controlling for potential confounders. The odds ratio for the highest quartile of 2-amino-3-methylimidazo [4,5-/|quinoline exposure was 3.34 (95% confidence interval 1.85-6.02). According to these results, meat intake and chemicals formed during the cooking process appear to be strong risk factors _n human breast carcinogenesis. Heterocyclic amines found in well-done meat require host-mediated metabolic activation before initiating DNA mutations and tumors in target organs. Polymorphic N-acetyltransferase-2 (NAT2) catalyses the activation of heterocyclic amines via O-acetylation, suggesting that NAT2 genotypes with high O-acetyltransferase activity (rapid/intermediate acetylator phenotype) increase the risk of breast cancer n women who consume well-done meat. To test this hypothesis, Deitz and Zheng28 o btained DNA samples and information on diet and other breast cancer risk factors from a nested case-control study of postmenopausal women. A significant dose- response relationship was observed between breast cancer risk and consumption : J well-done meat among women with the rapid/intermediate NAT2 genotype trend test, P = 0.003) that was not evident among women with the slow acetylator genotype (trend test, P = 0.22). Among women with the rapid/intermediate NAT2 genotype, consumption of well-done meat was a ssociated with a nearly >-fold (odds ratio, 7.6; 95% confidence interval, 1.1-50.4) elevated breast cancer risk compared with those consuming rare or medium-done meats. These results are consistent with a role for O-acetylation in the activation of heterocyclic amine carcinogens and support the hypothesis that the NAT2 acetylation polymorphism is a breast cancer risk factor among postmenopausal women with high levels of heterocyclic amine exposure. Also other studies have suggested that the rapid NAT2 acetylator phenotype is associated with breast cancer risk2930 or advanced disease at first presentation. Many heterocyclic amines are mammary carcinogens, and, a recent study31 found that another N-acetyltransferase polymorphism (NATlj was associated with breast cancer risk in individuals who consumed consistently well-done meat. To test the hypothesis that variations in the NAT1 gene are related to breast cancer risk, particularly among women who consume high levels of well-done meat, a nested case-control study was conducted by Zheng and Deitz32 in a prospective cohort study of 41 837 postmenopausal Iowa women. Genomic DNA samples obtained from 154 cases and 330 controls were assayed for 11 NAT1 alleles. The NAT 1*4 allele was the predominant allele observed in this study population, accounting for 73.2% (72.4% in cases versus 73.8% in controls) of the total alleles analysed. Compared to controls, breast cancer cases had a slightly higher frequency of the NATl*10allele (18.8% in cases versus 17.3% in controls) and a substantially higher frequency of the N ATI *11 allele (3.6% versus 1.2%). In multivariate analyses, they found a 30% (95% confidence interval (CI) = 0.8-1.9) elevated risk of breast cancer associated with the NAT1 * 10 allele and a nearly 4-fold (95% CI = 1.5-10.5) elevated risk associated with the NAT 1*11 allele. The positive association of breast cancer with the NAT 1*11 allele was more evident among those who consumed a high level of red meat (OR = 6.1, 95% CI = 1.1-33.2) or consistently consumed their red meatwell done (OR = 5.6, 95% CI = 0.5-62.7). It has been shown that the O-acetylation of 2-amino-1 -methyl-6-phenylimida- zo[4,5b]pyridine and 2-amino-3-methylimidazo-(4,5-/)quinoline, two of the most abundant heterocyclic amines in well-done meat, is largely carried out by NAT1 in human mammary glands33. Linos and Willett34 aimed to assess the relationship between red meat intake during adolescence and premenopausal breast cancer. They examined the incidence of invasive premenopausal breast cancer prospectively within the Nurses Health Study II. A total of 39 268 premenopausal women who completed a validated 124-item food frequency questionnaire on their diet during high school, were followed for 7 years, from 1998 to 2005. 455 cases of invasive premenopausal breast cancer were diagnosed between 1998 and 2005. Compared with women in the lowest quintile of red meat intake during high school, the multivariate-adjusted RR for the highest quintile of intake was 1.34 (95% CI, 0.94-1.89; Ptieni = 0.05). A significant linear association was observed with every additional 100 g of red meat consumed per day (RR, 1.20; 95% CI, 1.00-1.43; P = 0.05). This association was more pronounced in hormone receptor-positive tumors (RR, 1.36; 95% CI, 1.08-1.70; P = 0.008) and was not significant in hormon e receptor-negative tumors (RR, 0.99; 95% CI, 0.61-1.61,/> = 0.97). Several biological mechanisms may explain the positive association between red meat intake and hormone receptor-positive breast cancer risk. Because hormonal risk factors are more strongly related to hormone receptor-positive cancers, meat intake may operate through hormonal pathways. First, cooked or processed red meat is a source of carcinogens, such as heterocyclic amines. Second, exogenous hormone treatment of beef cattle for growth promotion, which is banned in European countries but not in the United States, has been of concern. Third, red meat is a source of heme iron, a highly bioavailable form of iron and a major source of stored body iron, which has been shown to synthesis and secretion of PRL in those cells. Together with previous reports that describe the potent estrogenicity of PhlPand its ability to influence progesterone receptor expression, c-Myc expression, and MAPK signal transduction pathway, the present findings provide clues about the mechanisms involved in the tissue-specific carcinogenicity of PhIP and, in particular, mammary carcinogenesis39. DISCUSSION Consumption of PhIP may play a role in the development of breast cancer. Experimental evidence over more than two decades has led to the proposal that heterocyclic aromatic amines (HAAs) may be causal factors in human breast cancer. High intake of deep-fried, well-done red meat may be associated with an increased risk of breast cancer, and the positive association may be modified by body weight. There is also evidence that nonhydrogenated soybean oil, if not used in high- temperature cooking, may be associated with a reduced risk of breast cancer. The data support the accumulating evidence that consumption of meats cooked by methods that promote carcinogen formation may increase risk of postmenopausal breast cancer. There is an association between the consumption of meat in general, meat prepared by different cooking methods and the dietary intake of heterocyclic aromatic amines (HCA) with the level of DNA adducts in the breast tissue. Meat intake and chemicals formed during the cooking process appear to be strong risk factors in human breast carcinogenesis. CONCLUSIONS The results of the studies presented are consistent with a role for O-acetylation in the activation of heterocyclic amine carcinogens and support the hypothesis that the NAT2 acetylation polymorphism is a breast cancer risk factor among postmenopausal women with high levels of heterocyclic amine exposure. There is also evidence suggesting that postmenopausal women with the NAT1*11 allele (aNATl allele) may be at increased risk of breast cancer, particularly if they smoked cigarettes or consumed a high level of well-done meat indicating the importance of the NAT1 enzyme in the in situ activation of heterocyclic amines in human breast epithelial cells, and point to the need in future studies to investigate potential interactions of genetic factors with intake of foods, food constituents, and nutrients in the etiology of cancer. Higher red meat intake in adolescence may increase the risk of premenopausal breast cancer. Red meat intake was strongly associated with an elevated risk of hormone receptor-positive breast cancer but not hormone receptor-negative cancers. Postmenopausal women who are homozygous for the His allele at codon 213 of the SULT1A1 gene may be at an increased risk of breast cancer, particularly'if they have risk factors related to higher endogenous estrogen exposure. 1