El papel de la obesidad, la actividad física y los factores dietéticos en el riesgo de cáncer de mama: la experiencia mexicana
Isabelle Romieu, MD, MPH, ScD; Martin Lajous, MD, MS
Instituto Nacional de Salud Pública. Cuernavaca, Morelos, México
We provide an overview of the role of adiposity, physical activity and diet in the risk for breast cancer in Mexican women. Lack of physical activity, diets high in carbohydrates and in glycemic load and low intake of folate and vitamin B12 have been shown to increase the risk of breast cancer in Mexican women, in particular postmenopausal breast cancer. Other dietary factors that may begin to play a more relevant role in breast cancer incidence in Mexico are alcohol intake and vitamin D status. Recommendations to maintain a healthy weight, practice moderate physical activity, decrease intake of rapidly absorbed carbohydrates and increase consumption of fruits and vegetables could have an important impact on the epidemic of breast cancer in Mexico.
Key words: breast cancer; adiposity; physical activity; carbohydrate; fats; alcohol; folic acid; Mexico
Se proporciona una revisión general del papel de la adiposidad, la actividad física y la dieta sobre el riesgo de cáncer de mama en mujeres mexicanas. La falta de actividad física, una dieta alta en hidratos de carbono y en carga glicémica y la baja ingesta de ácido fólico y vitamina B12 se han relacionado con un aumento en el riesgo de cáncer de mama en mujeres mexicanas, sobre todo en mujeres posmenopáusicas. Otros factores dietéticos que han tenido un papel más relevante en la incidencia de cáncer de mama en México son la ingesta de alcohol y las concentraciones de vitamina D. Las recomendaciones sobre cómo mantener un peso saludable, realizar actividad física moderada, disminuir la ingesta de hidratos de carbono de absorción rápida e incrementar el consumo de frutas y verduras podrían tener un impacto importante en la disminución de la epidemia de cáncer de mama en México.
Palabras clave: cáncer de mama, adiposidad, actividad física, carbohidratos, grasas, alcohol, ácido fólico; México
The incidence of breast cancer (BC) in Mexico is still relatively low as compared to Western countries but is increasing steadily. Breast cancer recently became the first cause of cancer mortality in Mexican women doubling between 1980 and 1990 from 6.4 to 13.1 per 100000 women among women 25 years and older and reaching 16.4 per 100000 women in 2007.1 This increase in mortality, while treatment has improved, reflects an increase in incidence linked in part to changes in women's lifestyles. Later age at first pregnancy, decreasing duration of lactation, fewer pregnancies, increasing hormone use for contraception and menopausal therapy, less active lifestyles and substitution of traditional dietary habits have probably contributed to this upward trend.2 Understanding the importance of these factors in the risk for BC is important because life style and dietary factors are potentially modifiable. The current review is a short summary of the available evidence relating adiposity, physical activity and dietary factors to BC focusing on factors that have been evaluated in Mexican women and on emerging factors that may prove to be of relevance in the future.
Overweight and obesity increase the risk of all-cause mortality and cancer mortality even among non-smokers.3 The relation between excess body weight and BC is complex: as compared to women who are not overweight, premenopausal overweight women are at a lower risk while postmenopausal overweight women are at a higher risk of BC. Pooled data from seven cohort studies comprising 703 premenopausal women with BC observed a relative risk 0.58 (95% CI: 0.34-1.00) for women with a body mass index1 greater or equal to 33 kg/m2 as compared to those with less than 21 kg/m2.2,4 In this same analysis, the relative risk of postmenopausal BC for the same comparison was 1.27 (95%CI: 1.03-1.55). These results are consistent with an analysis on 176 886 women from nine European countries from the EPIC5 and a recent analysis on twins observed that the inverse association in premenopausal women and the positive association in postmenopausal women may be even stronger after adjusting for genetic factors and early life environment.6 Several potential mechanisms may explain the differences observed between premenopausal and postmenopausal women. Among premenopausal women, the inverse association between BMI and BC was more clearly observed for ER+ tumors, suggesting that this association is likely due to sex steroid hormones.7 Premenopausal women may experience anovulation and may have a lower exposure to ovarian hormones due to anovulatory infertility.8
Among postmenopausal obese women, a large pooled analysis observed an almost twofold increase in the geometric mean of estradiol as compared to normal weight women, probably because of increased aromatization of adrenal androgens in adipose tissue.9 This same analysis reported that adjustment for estradiol level attenuated almost completely the linear association between BMI and BC risk.
Adult weight gain appears to be even a stronger determinant of BC than recent weight. For premenopausal women an increase of more than 25 kg was associated to a relative risk of 0.74 (95%CI: 0.54-1.03) and for postmenopausal women the relative risk was 1.41 (95%CI: 1.12-1.78).10 Among postmenopausal women, the association appears to be even stronger among women who never used hormone replacement therapy as compared to those who did suggesting that menopausal hormone therapy may have a residual effect on breast tissue and that the adiposity-mediated estrogenic effect may be dampened.
In recent years Mexico has experienced a dramatic rise in the prevalence of overweight and obesity. The prevalence rose from 33.4% in 1988 to 59.6% in 2000 to 71.9% in 2006 in adults. The increase is also dramatic among children, the prevalence increased by 33% in girls between 5 and 11 years of age between 1999 and 2006.11,12 There is no data on the association of adiposity and BC incidence in Mexico. However, given the magnitude of the obesity epidemic, the relevance of adiposity for postmenopausal BC and the susceptibility of the Mexican population to insulin resistance and metabolic syndrome13 we can expect adiposity to be an important driving factor in the increasing incidence of BC in Mexico.
Physical activity can affect hormonal levels14,15 and increase levels of sex hormone-binding globulin (SHBG), thereby reducing bioavailable estrogens.16 Increased physical activity also reduces insulin resistance and hyperinsulinemia,17 hypothesized to be related to BC.18 Many epidemiologic studies have evaluated the association between physical activity and BC. A recent study identified 19 cohort studies and 29 case-control studies amiable for analysis.19 After taking into account the quality of the studies, there is evidence of a least 20% lower risk of postmenopausal BC when comparing high to low leisure time activity. In contrast, results for premenopausal BC are inconclusive. More recently the EPIC study evaluated household physical activity, which is seldom measured, and observed a lower risk of BC in premenopausal [RR=0.71 (95%CI: 0.55-0.90), highest versus the lowest quartile] and postmenopausal women [RR=0.81 (95%CI: 0.70-0.93), highest versus the lowest quartile]. In the Iowa Women's Health Study, a strong inverse association for ER+/PR- BC was found and this association was not attenuated after adjustment for BMI.20 The suggestion that physical activity may affect BC risk through a hormone dependent pathway is supported by the inverse association observed between physical activity and several sex-hormones in the Women's Health Initiative.21
In a recent large case-control study in Mexico moderate physical activity (yoga, light biking, light walking) was inversely associated to BC risk. In postmenopausal women, there was a 9% reduction in the odds of BC for every hour per week increase of moderate physical activity. Among premenopausal women no association was observed [OR=0.99 (95% 0.94-1.05)].22 Regular recreational physical activity is uncommon in Mexican women. Only 16% of women exercise regularly and the national daily average of recreational physical activity for women is 5 minutes per day.23 Regular physical activity has clear cardiovascular benefits and may influence BC risk. The ongoing demographic transition from rural to urban areas is likely to result in lower overall physical activity in Mexico. Strategies to increase regular physical activity among Mexican women should be explored and further research on the impact of the lack of physical activity in this population is needed.
Few dietary factors have been consistently associated with BC risk. This apparent lack of association may be real, or may be due to measurement error exceeding the variation in the diet studied, and to a low heterogeneity of intake in the populations under study. While some dietary factors like fat and alcohol have been extensively investigated, other dietary factors potentially detrimental such as rapidly absorbed carbohydrates or potentially beneficial, such as vitamin D and folate have not been sufficiently explored.
Chronically raised insulin levels may increase carcinogenesis in breast tissue by directly stimulating insulin receptors or through a reduction in plasma and tissue levels of IGF binding proteins 1 and 2, which may in turn increase the availability of IGF-1.24 Experimental studies have found strong proliferative and antiapoptotic effects of IGF-1 in breast tissue.25 Elevated carbohydrate intake, and in particular rapidly-absorbed carbohydrates, may affect BC risk by maintaining a constant insulin demand through rapid increases in blood glucose. Nevertheless, these insulin-mediated mechanisms have not been fully supported by observational studies where circulating IGF-1 levels have not been associated to postmenopausal cancer and seem to be only marginally relevant for premenopausal cancer.26
There is no strong epidemiological evidence to support the role of carbohydrate intake or carbohydrate quality, as measured by overall glycemic index and glycemic load on overall BC risk.27-44 In the Nurses' Health Study, the largest study conducted to date, the relative risk of BC comparing extreme categories of carbohydrate intake was 0.97 (95%CI 0.87-1.08), glycemic index was 1.08 (95%CI 0.97-1.19) and glycemic load was 0.99 (95%CI 0.89-1.10).37 Nevertheless, there is a suggestion that carbohydrates may play a role when lifestyle factors, menopausal status and hormone receptor status are considered. In a recent large prospective study in France, overall glycemic index was associated with BC risk among overweight women (RR= 1.35 (95% CI: 1.00, 1.82)] when comparing extreme quartiles of intake32 suggesting that carbohydrates intake may be of relevance for BC in the presence of underlying insulin resistance. This study also found a direct association between carbohydrate intake and glycemic load and estrogen receptor-negative BC.
In a population-based case-control study in Mexico carbohydrate intake was directly associated with BC risk.30 Compared with women in the lowest quartile of total carbohydrate intake, the odds ratio of BC for women in the highest quartile was 2.22 [95% confidence interval (95% CI): 1.63-3.04]. This association was present in premenopausal and postmenopausal women. Results were further confirmed when the dietary glycemic load and glycemic index were evaluated. The odds ratio for all women comparing the highest to the lowest quartile of dietary glycemic load was 1.62 (95% CI 1.13-2.32). However, overall glycemic index was not significantly associated with BC risks. Carbohydrates account for 64% of caloric intake in the Mexican population.45 This large variability in intake is not observed in western populations and may account for the apparent discrepancy between observations made in Mexico and elsewhere. It is also likely that high intake of refined carbohydrates could have stronger associations with risk of BC in populations genetically susceptible to insulin resistance, such as in Mexico, particularly when combined with low levels of physical activity and obesity.
The role of dietary fat as a risk factor for BC is controversial. Animal feeding studies have shown for several decades that high-fat diets induce mammary carcinogenesis.46 Experimental and epidemiologic data have been unable to clearly define the biological pathways that would lead to carcinogenesis.47,48 Epidemiological studies have yielded conflicting results. Initial evidence from ecologic and case-control studies suggested a direct association between fat intake and BC risk.49,50 However, most subsequent prospective cohort studies have not lent strong support to this hypothesis. A pooled analysis of eight prospective cohorts that included 351 821 women and 7 329 cases reported no clear evidence of an association between total fat intake and pre and postmenopausal BC but the risk ratio for saturated fat intake was 1.09 (95%CI 1.00-1.19).51 The controversy persists. A recent analysis in the Nurses' Health Study evaluated this hypothesis with a 20 year follow-up using six repeated measures of dietary intake and found a null association.52 In contrast, a well-conducted large cohort with close to 200000 participants found evidence of a direct association.53 Furthermore, in the large Women's Health Initiative (WHI) randomized trial low-fat diet was related to a 9% lower risk of BC in the intervention group.54 Results of this trial are difficult to interpret because actual fat intake between the intervention and the control group was small. The difference in BC incidence between groups could be explained by the observed reduction of weight and an increase in fruit and vegetable intake in the intervention group.
Total fat intake appears to have a relatively modest association with BC risk if at all. In the absence of strong evidence of the underlying biologic pathways that lead to carcinogenesis, fat restriction as a strategy to reduce BC risk is not warranted. In Mexico two case-control studies30,55 did not observed an association for saturated fat yet a inverse association was observed for polyunsaturated fat among postmenopausal women when comparing extreme quartiles of intake [OR= 0.37 (95% CI 0.20-0.66) 30 and OR= 0.10 (95% CI 0.02-0.39).55 Nevertheless, more research is needed to assess the association of fat intake during childhood and adolescence as well as different types of fat.
Alcohol is the dietary factor for which the association with BC is most consistent and biological mechanisms are more clearly defined. Prospective studies involving several thousand BC cases report that increasing alcohol consumption is associated with a moderate linear increase in the risk of BC ranging from 3 to 9% for one additional drink per day (10 g).56,57 The association is present in both premenopausal and postmenopausal women, does not vary by type of alcoholic beverage, 56,57 does not seem to depend on drinking frequency56,58 and is mostly restricted to estrogen positive breast tumors.59 The relevant timing of exposure seems to be recent alcohol intake: alcohol intake during adolescence60,61 and after adjustment for current alcohol consumption, intake in the 20s, 30s and 40s age periods is not associated to subsequent BC.56 The best supported mechanism underlying this association is related circulating estrogen levels. Experimental studies have shown that addition of alcohol to BC cells results in estrogen-mediated signaling and proliferation.62,63 Controlled feeding trials have shown that moderate alcohol intake increases circulating estrogen levels in both pre and postmenopausal women.64,65 Alcohol intake in Mexican women is still relatively low, less than 5% of middle age women report weekly consumption of alcohol.12 However, 10% of adolescent girls aged 16 to 19 report alcohol consumption at least once a week. Elevated alcohol intake in younger women may result in alcohol intake patterns later in life that may increase BC risk.
Folate participates in DNA metabolism in the synthesis of purines and thymidilate and is a methyl donor for DNA methylation reactions. Low levels of folate may result in a disruption of DNA repair and replication processes and in abnormal methylation and gene expression.66 Most prospective studies do not provide evidence of an association between folate intake and BC risk67,68 and results from the Nurses' Health Study are only suggestive of an inverse association with circulating folate levels.69 High intake of folate as well as circulating levels may be associated with lower risk of BC among moderate to high alcohol-drinkers.69,70 Ethanol may produce a physiologic deficiency that affects one-carbon metabolism by reducing folate absorption in the gastrointestinal tract or by inhibiting enzymatic activity.66 It is possible that the benefit of folate may only be observable in individuals with low folate status. This is supported by observations in populations where folate fortification is not present and vitamin supplementation is infrequent.71-75 In a population-based case-control study in Mexico where folate intake is low, the odds ratio for the highest quartile of folate intake compared to the lowest was 0.62 (95% CI, 0.45-0.90).75 Folate may play a dual role in human cancer etiology by confering protection in early carcinogenesis and promoting cancer growth later in the carcinogenic process. In a screening trial in the United States after widespread folate fortification a significant increase in BC risk with increasing folate intake was observed [RR=1.32 (95%CI: 1.04-1.68) comparing the highest to the lowest level of intake].76 In this population total folate intake was several times higher than what was observed in other studies and the increased risk was mostly related to folic acid supplementation. Furthermore, there is a suggestion that vitamin B12, a co-enzyme in folate metabolism, may be a associated to lower risk of BC and that low vitamin B12 intake may reduce the apparent protection in the risk for BC conferred by folate.75-78
Dietary folate comes primarily from grean leafy vegetables, citrus fruits and legumes.79 Vegetable and fruit intake in Mexican women is low (97% of Mexican women consume < 400 g/day) and in 1999 median folate intake among Mexican women was 221 µg/day, which is close to half of the US RDA.45,80 Mexicans have the highest reported prevalence of homozygous TT genotype for the 677CT transition in the methylenetetrahydrofolate reductase (MTHFR) gene (32%).81 Among individuals with this variant, low folate intake has been associated to a higher risk of BC as compared to other genotypes.71 It is likely that both low dietary folate intake and a genetic susceptibility in the Mexican population may partially contribute to the increase in the incidence of BC in Mexican women as observed for gastric cancer (GC). A significant increase in GC risk was found among carriers of the 677TT genotype compared with those with the 677CC genotype [odds ratio (OR) 1.62, 95% confidence interval (CI) 1.00-2.59].82 Vitamin deficiencies are potentially modifiable risk factors which can be addressed by supplementation and fortification of food. Folate deficiency is associated to other health outcomes and research to evaluate alternatives to address this problem should be conducted. However caution is required given results from trial that suggest that folate possesses dual modulatory effects on the development and progression of cancer depending on the timing and dose of folate intervention.83
Vitamin D has recently emerged as potentially an important determinant of BC; however, information is still scant. Vitamin D is a fat-soluble vitamin and a hormone present in food in two forms: cholecalciferol (D3) from animal sources and ergocalciferol (D2) from plant sources. The main source of vitamin D3 in humans is epidermally-generated through the exposure to UV light.84 Vitamins D2 and D3 are metabolized to 25-hydroxyvitamin D [25-(OH) D] in the liver and then transformed in the kidneys into the biologically active and closely regulated 1,25-dihydroxyvitamin D [1,25-(OH2) D].85 Experimental studies have shown that 1,25-(OH2) D can inhibit cellular proliferation, induce differentiation and apoptosis, inhibit angiogenesis in normal and cancer cells and modulate gene expression.86
Results from epidemiologic studies suggest an inverse association between vitamin D intake and BC, particularly among premenopausal women. The risk ratio for premenopausal BC comparing extreme categories of intake was 0.72 (95%CI: 0.55-0.94) in the Nurses' Health Study87 and 0.65 (95%CI: 0.42-1.00) in the Women's Health Study.88 A pooled analysis found a strong linear inverse association between serum 25(OH)D and BC risk;89 while results for 1,25-(OH2) D were less clear.
Vitamin D status appears to be affected by factors associated to intake, UV light exposure and factors that may affect its metabolism. Among men in the US race, latitude of residence, physical activity, body mass index, dietary intake and season explained 28% of the variability.90 Among Mexican women, intake of vitamin D is well bellow the Recommended Dietary Allowance of 5µg/day45 and the finding that Mexican-Americans have a significantly lower level of circulating vitamin D as compared to US whites91 is supported by the observation that individuals with pigmented skin may have deficient vitamin D levels even when sun exposure is abundant.92
There is no information on circulating levels of vitamin D in Mexico. High exposure to UV light due to Mexico's latitude may result in a vitamin D-replete population with little variability. However, a setting with low dietary intake and no fortification, skin pigmentation, high prevalence of obesity and low physical activity circulating levels of vitamin D may be suboptimal. Vitamin D may therefore potentially contribute to BC incidence in Mexico.
Dietary fiber and other foods and nutrients
Fiber could play a role on the risk of BC by decreasing the intestinal reabsorption of estrogen and therefore lowering its circulating levels.93 Fiber intake has also been related to an increase in serum levels of insulin growth factor binding protein-3 (IGFBP-3), the main protein carrier for IGF-1.94 However to date there is no clear data on the role of fiber on the risk of BC.95 In Mexico, case-control studies suggest a protective effect of fiber intake on BC risk.30,55 Tea has been hypothesized to be associated with a reduced risk of BC through the anticarcinogenic effect of polyphenolic flavonoids.96 A meta-analysis found an inverse association between green tea and BC, the summary odds ratio for the highest versus the lowest exposure level was 0.78 (95%CI: 0.61-0.98).96 However, results for black tea have been consistently null and a prospective analysis of total polyphenol intake did not yield significant findings.97-99 Interest in coffee as a potential determinant of BC originated from observation that women who reduced consumption of coffee experienced a regression of fibrocystic disease of the breast, a known risk factor for BC.100 However, results for coffee intake and BC on most large prospective cohorts are essentially null.101,102 In Sweden, the largest per capita consumer of coffee, women who consumed four or more cups of coffee a day had a relative risk of 0.94 (95% CI: 0.75-1.28) as compared to women who had one cup a week or less.103 Phytoestrogens have been evaluated as nutrients that may potentially reduce BC risk. Isoflavonoids, coumestrol and lignans are mainly found in soybeans, cereals and grains and these nutrients have been hypothesized to act as weak estrogen agonist or antagonists.104,105 A recent meta analysis reported a pooled relative risk comparing high and low soy intake of 0.86 (95%CI: 0.75-0.99).106 In Mexico, case-control studies observed a protective effect of phytoestrogen intake on BC risk.107,108 High dietary intake of lignans (lariciresinol and pinoresinol) was associated with a significant reduction for premenopausal BC (high v. low tertile: OR = 0.32, 95 % CI 0.10, 0.99 and OR=0.19, 95% CI 0.06-0.62).108
Lifestyle and dietary habits in Mexican population have dramatically changed in the last 20 years as reflected by an increased prevalence of obesity in both urban and rural populations. Based on the 2006 National Nutrition Survey (ENSANUT 2006)109 35% of women over age 20 are overweight (BMI 25 to 29) and 31.7% are obese (BMI>=30). This represents a 41% and a 160% increase in the prevalence of overweight and obesity in just a decade.110 Moreover, Mexicans appear to have a genetic susceptibility to insulin resistance and altered carbohydrate and lipid metabolism.111-113 Carbohydrates are the major source of calories in the Mexican population with a mean daily carbohydrate intake of 357 g/day, equivalent to 64% of total caloric intake.45 Low intakes of vegetables and fruits (97% of Mexican women consume < 400 g/day) and animal products and increasing consumption of processed foods may account for the high prevalence of micronutrient deficiencies observed in Mexican women such as folate, vitamin B127 and n-3 PUFA. Thirty five percent of Mexican women had deficient serum levels of folate and 17% had low levels of vitamin B12 in serum.
Obesity, lack of physical activity, high intake of carbohydrate, high glycemic load, low fiber intake, low intake of folate and vitamin B12 have been shown to increase the risk of BC in Mexican women, in particular postmenopausal BC. Other nutrients such as omega3 fatty acid, phytoestrogen of low intake in the Mexican population and vitamin D could also play an important role in the risk for BC.
Recommendations to loose weight, practice moderate physical activity and decrease intake of fast absorbed carbohydrate could have an important impact on the epidemic of BC. In addition, increased intake of folate and vitamin B12 in subjects with deficiency could also have a protective effect. To improve our knowledge on these and other factors, we recently implemented a large cohort study of Mexican teachers (EsMaestra) whom we plan to follow biannually over 10 years or more. The prospective assessment of lifestyle and diet will provide the adequate setting to evaluate causal factors of BC risk in Mexican women.
1. Secretaría de Salud. Avances en las metas estratégicas del Programa Sectorial de Salud 2007-2012. En: Rendición de cuentas en Salud 2007. Mexico, D. F.: Secretaría de Salud, 2008:18-46.
2. López-Ríos O, Lazcano-Ponce E, Tovar V, Hernández-Ávila M. La epidemiología de cáncer de mama en México. ¿Consecuencia de la transición demográfica? Salud Publica Mex 1997;39:259-265.
3. Hu FB, Willett WC, Li T, Stampfer MJ, Colditz GA, Manson JE. Adiposity as compared with physical activity in predicting mortality among women. N Engl J Med 2004;351:2694-2703.
4. Van den Brandt PA, Spiegelman D, Yaun SS, Adami HO, Beeson L, Folsom AR, et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 2000;152:514-527.
5. Lahmann PH, Hoffmann K, Allen N, van Gils CH, Khaw KT, Tehard B, et al. Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer And Nutrition (EPIC). Int J Cancer 2004;111:762-771.
6. Lundqvist E, Kaprio J, Verkasalo PK, Pukkala E, Koskenvuo M, Söderberg KC, et al. Co-twin control and cohort analyses of body mass index and height in relation to breast, prostate, ovarian, corpus uteri, colon and rectal cancer among Swedish and Finnish twins. Int J Cancer 2007;121:810-814.
7. Michels KB, Terry KL, Willett WC. Longitudinal study on the role of body size in premenopausal breast cancer. Arch Intern Med 2006;166118:2395-2402.
8. Rich-Edwards JW, Goldman MB, Willett WC, Hunter DJ, Stampfer MJ, Colditz GA, et al. Adolescent body mass index and infertility caused by ovulatory disorder. Am J Obstet Gynecol 1994;171:171-177.
9. Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, et al. Endogenous Hormones Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003;95:1218-1226.
10. Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, et al. Dual effects of weight and weight gain on breast cancer risk. JAMA 1997;278:1407-1411.
11. Rivera JA, Barquera S, Campirano F, Campos I, Safdie M, Tovar V. Epidemiological and nutritional transition in Mexico: rapid increase of non-communicable chronic diseases and obesity. Public Health Nutr 2002;5:113-122.
12. Olaiz G, Barquera S, Shamah T, Aguilar C, Cravioto P, Lopez P, et al. Encuesta Nacional de Salud 2000. Tomo I. Vivienda, población y utilización de servicios de salud. Cuernavaca, Morelos, México: Instituto Nacional de Salud Pública, 2003.
13. Edwards KL, Hutter CM, Wan JY, Kim H, Monks SA. Genome-wide linkage scan for the metabolic syndrome: the GENNID study. Obesity (Silver Spring) 2008;16:1596-1601.
14. Siiteri PK. Adipose tissue as a source of hormones. Am J Clin Nutr 1987;45:S277-S282.
15. Cauley JA, Gutai JP, Kuller LH, LeDonne D, Powell JG. The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol 1989;129:1120-1131.
16. An P, Rice T, Gagnon J, Hong Y, Leon AS, Skinner JS, et al. A genetic study of sex hormone-binding globulin measured before and after a 20-week endurance exercise training program: the HERITAGE Family Study. Metabolism 2000;49:1014-1020.
17. Stoll BA. Adiposity as a risk determinant for postmenopausal breast cancer. Int J Obes Relat Metab Disord 2000;24:527-533.
18. Kaas R. Plasma insulin, IGF-I and breast cancer. Gynecol Obstet Fertil 2001;29:185-191.
19. Monninkhof EM, Elias SG, Vlems FA, van der Tweel I, Schuit AJ, Voskuil DW, et al. Physical activity and breast cancer: a systematic review. Epidemiology 2007;18:137-157.
20. Bardia A, Hartmann LC, Vachon CM, Vierkant RA, Wang AH, Olson JE, et al. Recreational physical activity and risk of postmenopausal breast cancer based on hormone receptor status. Arch Intern Med 2006;166:2478-2483.
21. McTiernan A, Wu L, Chen C, Chlebowski R, Mossavar-Rahmani Y, Modugno F, et al. Relation of BMI and physical activity to sex hormones in postmenopausal women. Obesity (Silver Spring) 2006;14:1662-1677.
22. Ortiz-Rodríguez SP, Torres-Mejía G, Mainero-Ratchelous F, Angeles-Llerenas A, López-Caudana AE, Lazcano-Ponce E, et al. Actividad física y riesgo de cáncer de mama en mujeres mexicanas. Salud Publica Mex 2008;50:126-135.
23. Hernández B, de Haene J, Barquera S, Monterrubio E, Rivera J, Shamah T, et al. Factores asociados con la actividad física en mujeres mexicanas en edad reproductiva. Rev Panam Salud Publica 2003;144(4):235-245.
24. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579-591.
25. Yanochko GM, Eckhart W. Type I insulin-like growth factor receptor over-expression induces proliferation and anti-apoptotic signaling in a three-dimensional culture model of breast epithelial cells. Breast Cancer Res 2006;8:R18.
26. Fletcher O, Gibson L, Johnson N, Altmann DR, Holly JM, Ashworth A, et al. Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:2-19.
27. Yu SZ, Lu RF, Xu DD, Howe GR. A case-control study of dietary and nondietary risk factors for breast cancer in Shanghai. Cancer Res 1990;50:5017-5021.
28. Silvera SA, Jain M, Howe GR, Miller AB, Rohan TE. Dietary carbohydrates and breast cancer risk: a prospective study of the roles of overall glycemic index and glycemic load. Int J Cancer 2005;114:653-658.
29. Sieri S, Pala V, Brighenti F, Pellegrini N, Muti P, Micheli A, et al. Dietary glycemic index, glycemic load, and the risk of breast cancer in an Italian prospective cohort study. Am J Clin Nutr 2007;86:1160-1166.
30. Romieu I, Lazcano-Ponce E, Sanchez-Zamorano LM, Willett W, Hernandez-Avila M. Carbohydrates and the risk of breast cancer among Mexican women. Cancer Epidemiol Biomarkers Prev 2004;13:1283-1289.
31. Lajous M, Romieu I, Lazcano-Ponce E, Sanchez-Zamorano LM, Willett W, Hernandez-Avila M. Glycemic load, glycemic index and the risk of breast cancer among mexican women. Cancer Causes and Control 2005;16:1165-1169.
32. Lajous M, Boutron-Ruault MC, Fabre A, Clavel-Chapelon F, Romieu I. Carbohydrate intake, glycemic index, glycemic load, and risk of postmenopausal breast cancer in a prospective study of French women. Am J Clin Nutr 2008;87:1384-1391.
33. Kushi LH, Sellers TA, Potter JD, Nelson CL, Munger RG, Kaye SA, et al. Dietary fat and postmenopausal breast cancer. J Natl Cancer Inst 1992;84:1092-1099.
34. Knekt P, Albanes D, Seppänen R, Aromaa A, Järvinen R, Hyvönen L, et al. Dietary fat and risk of breast cancer. Am J Clin Nutr 1990;52:903-908.
35. Jonas CR, McCullough ML, Teras LR, Walker-Thurmund KA, Thun MJ, Calle EE. Dietary glycemic index, glycemic load, and risk of incident breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2003;12(573-577).
36. Horn-Ross PL, Hoggatt KJ, West DW, Krone MR, Stewart SL, Anton H, et al. Recent diet and breast cancer risk: the California Teachers Study (USA). Cancer Causes Control 2002;13:407-415.
37. Holmes MD, Liu S, Hankinson SE, Colditz GA, Hunter DJ, Willett WC. Dietary carbohydrates, fiber and breast cancer. Am J Epidemiol 2004;159:732-739.
38. Higginbotham S, Zhang ZF, Lee IM, Cook NR, Buring JE, Liu S. Dietary glycemic load and breast cancer risk in the Women's Health Study. Cancer Epidemiol Biomarkers Prev 2004;13:65-70.
39. Giles GG, Simpson JA, English DR, Hodge AM, Gertig DM, Macinnis RJ, et al. Dietary carbohydrate, fibre, glycaemic index, glycaemic load and the risk of postmenopausal breast cancer. Int J Cancer 2006;118:1843-1847.
40. Folsom AR, Demissie Z, Harnack L. Correspondence re: C. R. Jonas et al., Dietary glycemic index, glycemic load, and risk of incident breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2003;12:1547.
41. Dos Santos Silva I, Mangtani P, McCormack V, Bhakta D, Sevak L. Lifelong vegetarianism and risk of breast cancer: a population-based case-control study among South Asian migrant women living in England. Int J Cancer 2002;99:238-244.
42. Cho E, Spiegelman D, Hunter DJ, Chen WY, Colditz GA, Willett WC. Premenopausal dietary carbohydrate, glycemic index, glycemic load and fiber in relation to risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2003;12:1153-1158.
43. Barrett-Connor E, Friedlander NJ. Dietary fat, calories, and the risk of breast cancer in postmenopausal women: a prospective population-based study. J Am Coll Nutr 1993;12:390-399.
44. Augustin LS, Dal Maso L, La Vechia C, Parpinel M, Negri E, Vaccarella S, et al. Dietary glycemic index and glycemic load, and breast cancer risk: A case-control study. Ann Oncol 2001;12:1533-1538.
45. Rivera-Dommarco J, Shamah-Levy T, Villalpando-Hernández S, González-Cossio T, Hernandez-Prado B, Sepulveda J. Encuesta Nacional de Nutrición 1999. Estado nutricio de niños y mujeres en México. Cuernavaca, Morelos, México: Instituto Nacional de Salud Pública, 2001.
46. Fay MP, Freedman LS. Meta-analyses of dietary fats and mammary neoplasms in rodent experiments. Breast Cancer Res Treat 1997;46:215-223.
47. Wu AH, Pike MC, Stram DO. Meta-analysis: dietary fat intake, serum estrogen levels, and the risk of breast cancer. J Natl Cancer Inst 1999;91:529-534.
48. Woutersen RA, Appel MJ, van Garderen-Hoetmer A, Wijnands MV. Dietary fat and carcinogenesis. Mutat Res 1999;443:111-127.
49. Boyd NF, Stone J, Vogt KN, Connelly BS, Martin LJ, Minkin S. Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature. Br J Cancer 2003;89:1672-1685.
50. Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer 1975;15:617-631.
51. Smith-Warner SA, Spiegelman D, Adami HO, Beeson WL, van den Brandt PA, Folsom AR, et al. Types of dietary fat and breast cancer: a pooled analysis of cohort studies. Int J Cancer 2001;92:767-774.
52. Kim EH, Willett WC, Colditz GA, Hankinson SE, Stampfer MJ, Hunter DJ, et al. Dietary fat and risk of postmenopausal breast cancer in a 20-year follow-up. Am J Epidemiol 2006;164:990-997.
53. Thiebaut AC, Kipnis V, Chang SC, Subar AF, Thompson FE, Rosenberg PS, et al. Dietary fat and postmenopausal invasive breast cancer in the National Institutes of Health-AARP Diet and Health Study cohort. J Natl Cancer Inst 2007;99:451-462.
54. Prentice RL, Thomson CA, Caan B, Hubbell FA, Anderson GL, Beresford SA, et al. Low-fat dietary pattern and cancer incidence in the women's health initiative dietary modification randomized controlled trial. J Natl Cancer Inst 2007;99:1534-1543.
55. Bonilla-Fernandez P, Lopez-Cervantes M, Torres-Sanchez LE, Tortolero-Luna G, Lopez-Carrillo L. Nutritional factors and breast cancer in Mexico. Nutr Cancer 2003;45:148-155.
56. Tjonneland A, Christensen J, Olsen A, Stripp C, Thomsen BL, Overvad K, et al. Alcohol intake and breast cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control 2007;18:361-373.
57. Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998;279:535-540.
58. Horn-Ross PL, Canchola AJ, West DW, Stewart SL, Bernstein L, Deapen D, et al. Patterns of alcohol consumption and breast cancer risk in the California Teachers Study cohort. Cancer Epidemiol Biomarkers Prev 2004;13:405-411.
59. Zhang SM, Lee IM, Manson JE, Cook NR, Willett WC, Buring JE. Alcohol consumption and breast cancer risk in the Women's Health Study. Am J Epidemiol 2007;165:667-676.
60. Marcus PM, Newman B, Millikan RC, Moorman PG, Baird DD, Qaqish B. The associations of adolescent cigarette smoking, alcoholic beverage consumption, environmental tobacco smoke, and ionizing radiation with subsequent breast cancer risk (United States). Cancer Causes Control 2000;11:271-278.
61. Holmberg L, Baron JA, Byers T, Wolk A, Ohlander EM, Zack M, et al. Alcohol intake and breast cancer risk: effect of exposure from 15 years of age. Cancer Epidemiol Biomarkers Prev 1995;4:843-847.
62. Singletary KW, Frey RS, Yan W. Effect of ethanol on proliferation and estrogen receptor-alpha expression in human breast cancer cells. Cancer Lett 2001;165:131-137.
63. Fan S, Meng Q, Gao B, Grossman J, Yadegari M, Goldberg ID, et al. Alcohol stimulates estrogen receptor signaling in human breast cancer cell lines. Cancer Res 2000;60:5636-639.
64. Reichman ME, Judd JT, Longcope C, Schatzkin A, Clevidence BA, Nair PP, et al. Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women. J Natl Cancer Inst 1993;85:722-727.
65. Dorgan JF, Baer DJ, Albert PS, Judd JT, Brown ED, Corle DK, et al. Serum hormones and the alcohol-breast cancer association in postmenopausal women. J Natl Cancer Inst 2001;93:710-715.
66. Mason JB, Choi SW. Folate and carcinogenesis: developing a unifying hypothesis. Adv Enzyme Regul 2000;40:127-141.
67. Lewis SJ, Harbord RM, Harris R, Smith GD. Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. J Natl Cancer Inst 2006;98:1607-1622.
68. Larsson SC, Giovannucci E, Wolk A. Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 2007;99:64-76.
69. Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine and risk of breast cancer. J Natl Cancer Inst 2003;95:373-380.
70. Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999;281:1632-1637.
71. Shrubsole MJ, Gao YT, Cai Q. MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from Shanghai Breast Cancer Study. Cancer Epidemiol Biomark Prev 2004;13:190-196.
72. Ronco A, De Stefani E, Boffetta P, Deneo-Pellegrini H, Mendilaharsu M, Leborgne F. Vegetables, fruits, and related nutrients and risk of breast cancer: a case-control study in Uruguay. Nutr Cancer 1999;35:111-119.
73. Negri E, La Vecchia C, Franceschi S. Re: dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:1270-1271.
74. Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake of selected micronutrients and breast-cancer risk. Int J Cancer 2001;91:260-263.
75. Lajous M, Lazcano E, Hernandez M, Willett W, Romieu I. Folate, vitamin B6 and vitamin B12 intake and the risk of breast cancer among Mexican women. Cancer Epidemiol Biomarkers Prev 2006;15:443-448.
76. Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS, et al. Folate intake, alcohol use, and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Am J Clin Nutr 2006;83:895-904.
77. Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, et al. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 2001;61:7136-7141.
78. Lajous M, Romieu I, Sabia S, Boutron-Ruault MC, Clavel-Chapelon F. Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women. Cancer Causes Control 2006;17:1209-1213.
79. Linus Pauling Institute. Micronutrient Information Center. http://lpi.oregonstate.edu/infocenter/vitamins/fa/, Access December 10, 2008.
80. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin Bg, Folate, Vitamin B12, Pantothinic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998.
81. Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Renlund M, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet 2003;40:619-625.
82. Lacasaña-Navarro M, Galván-Portillo M, Chen J, Lopez-Cervantes M, Lopez-Carrillo L. Methylenetetrahydrofolate reductase 677C>T polymorphism and gastric cancer susceptibility in Mexico. Eur J Cancer 2006;42:528-533.
83. Kim YI. Does a high folate intake increase the risk of breast cancer? Nutr Rev 2006;64:468-475.
84. Welsh J. Vitamin D and prevention of breast cancer. Acta Pharmacol Sin 2007;28:1373-1382.
85. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-281.
86. Cui Y, Rohan TE. Vitamin D, calcium, and breast cancer risk: a review. Cancer Epidemiol Biomarkers Prev 2006;15:1427-1437.
87. Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC. Intake of dairy products, calcium, and vitamin d and risk of breast cancer. J Natl Cancer Inst 2002;94:1301-1311.
88. Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007;167:1050-1059.
89. Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol 2007;103:708-711.
90. Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451-459.
91. Kant AK, Graubard BI. Ethnicity is an independent correlate of biomarkers of micronutrient intake and status in American adults. J Nutr 2007;137:2456-2463.
92. Goswami R, Gupta N, Goswami D, Marwaha RK, Tandon N, Kochupillai N. Prevalence and significance of low 25-hydroxyvitamin D concentrations in healthy subjects in Delhi. Am J Clin Nutr 2000;72:472-475.
93. Cohen LA. Dietary fiber and breast cancer. Anticancer Res 1999;19:3685-3688.
94. Probst-Hensch NM, Wang H, Goh VH, Seow A, Lee HP, Yu MC. Determinants of circulating insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations in a cohort of Singapore men and women. Cancer Epidemiol Biomarkers Prev 2003;12:739-746.
95. Mattisson I, Wirfalt E, Johansson U, Gullberg B, Olsson H. Intakes of plant foods, fibre and fat and risk of breast cancer--a prospective study in the Malmo Diet and Cancer cohort. Br J Cancer 2004;90:122-127.
96. Yang CS, Maliakal P, Meng X. Inhibition of carcinogenesis by tea. Annu Rev Pharmacol Toxicol 2002;42:25-54.
97. Sun CL, Yuan JM, Koh WP. Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies. Carcinogenesis 2006;27:1310-1315.
98. Baker JA, Beehler GP, Sawant AC, Jayaprakash V, McCann SE, Moysich KB. Consumption of coffee, but not black tea, is associated with decreased risk of premenopausal breast cancer. J Nutr 2006;136:166-171.
99. Adebamowo CA, Hu FB, Cho E, Spiegelman D, Holmes MD, Willett WC. Dietary patterns and the risk of breast cancer. Ann Epidemiol 2005;15:789-795.
100. Marshall LM, Hunter DJ, Connolly JL, Schnitt SJ, Byrne C, London SJ, et al. Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types. Cancer Epidemiol Biomarkers Prev 1997;6:297-301.
101. Folsom AR, McKenzie DR, Bisgard KM, Kushi LH, Sellers TA. No association between caffeine intake and postmenopausal breast cancer incidence in the Iowa Women's Health Study. Am J Epidemiol 1993;138:380-383.
102. Hunter D, Manson JE, Stampfer MJ, Colditz GA, Rosner B, Hennekens CH. A prospective study of caffeine, coffee, tea and breast cancer. Am J Epidemiol 1992;136:1000-1001.
103. Michels KB, Holmberg L, Bergkvist L, Wolk A. Coffee, tea, and caffeine consumption and breast cancer incidence in a cohort of Swedish women. Ann Epidemiol 2002;12:21-26.
104. Messina M, McCaskill-Stevens W, Lampe JW. Addressing the soy and breast cancer relationship: review, commentary, and workshop proceedings. J Natl Cancer Inst 2006;98:1275-1284.
105. Dixon RA. Phytoestrogens. Phytoestrogens. Annu Rev Plant Biol 2004;55:225-261.
106. Trock BJ, Hilakivi-Clarke L. Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 2006;98:459-471.
107. Torres-Sanchez L, Lopez-Carrillo L, Lopez-Cervantes M, Rueda-Neria C, Wolff MS. Food sources of phytoestrogens and breast cancer risk in Mexican women. Nutr Cancer 2000;37:134-139.
108. Torres-Sanchez L, Galvan-Portillo M, Wolff MS, Lopez-Carrillo L. Dietary consumption of phytochemicals and breast cancer risk in Mexican women. Public Health Nutr 2008:1-7.
109. Olaiz-Fernández G, Rivera-Dommarco J, Shamah-Levy T, Rojas R, Villalpando-Hernández S, Hernández-Avila M, et al. Encuesta Nacional de Salud y Nutrición 2006. Cuernavaca: Instituto Nacional de Salud Pública, 2006.
110. Rivera JA, Sepulveda-Amor J. Conclusions from the Mexican National Nutrition Survey 1999: translating results into nutrition policy. Salud Publica Mex 2003;45:S565-S575.
111. Mitchell BD, Blangero J, Comuzzie AG, Almasy LA, Shuldiner AR, Silver K, et al. A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans. J Clin Inv 1998;101(3):584-387.
112. Liu S, Manson JE, Stampfer MJ, Holmes MD, Hu FB, Hankinson SE, et al. Dietary glycemic load assessed by food frequency questionnaire in relation to plasma high-density lipoprotein cholesterol and fasting triglycerides among postmenopausal women. Am J Clin Nutr 2001;73:560-566.
113. Clement K, Vaisse C, Manning B, Basdevant A, Guy-Grand B, Ruiz J, et al. Genetic variation in the beta 3-adrenegic receptor and an increased capacity to gain weight in patients with morbid obesity. NEJM 1995;333:352-354.
Address reprint requests to:
Instituto Nacional de Salud Pública
Av. Universidad No. 655
Col. Santa María Ahuacatitlán, 62508
Cuernavaca, Morelos, México
Received on: November 28, 2008
Accepted on: December 17, 2008