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Cancer epidemiol biomarkers prev veronique chajes, Gabriela. Torres-Mejia, carine biessy, et al. Breast Cancer in Mexican Women: Impact of Obesity Status -6 Polyunsaturated Fatty Acid. Intakes and the risk of o -3 and o -6. This article cites by 31 articles, 11 of which you can access for free at: Citing articles #related-urls
Cancer epidemiol biomarkers prev veronique chajes, Gabriela. Torres-Mejia, carine biessy, et al. Breast Cancer in Mexican Women: Impact of Obesity Status -6 Polyunsaturated Fatty Acid. Intakes and the risk of o -3 and o -6. This article cites by 31 articles, 11 of which you can access for free at: Citing articles #related-urls
Cancer epidemiol biomarkers prev veronique chajes, Gabriela. Torres-Mejia, carine biessy, et al. Breast Cancer in Mexican Women: Impact of Obesity Status -6 Polyunsaturated Fatty Acid. Intakes and the risk of o -3 and o -6. This article cites by 31 articles, 11 of which you can access for free at: Citing articles #related-urls
2012;21:319-326. Published OnlineFirst December 22, 2011.
Cancer Epidemiol Biomarkers Prev
Vronique Chajs, Gabriela Torres-Meja, Carine Biessy, et al.
Breast Cancer in Mexican Women: Impact of Obesity Status -6 Polyunsaturated Fatty Acid Intakes and the Risk of -3 and
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. permissions@aacr.org To request permission to re-use all or part of this article, contact the AACR Publications Department at on May 14, 2014. 2012 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst December 22, 2011; DOI: 10.1158/1055-9965.EPI-11-0896 on May 14, 2014. 2012 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst December 22, 2011; DOI: 10.1158/1055-9965.EPI-11-0896 Research Article v-3 and v-6 Polyunsaturated Fatty Acid Intakes and the Risk of Breast Cancer in Mexican Women: Impact of Obesity Status V eronique Chaj es 1 , Gabriela Torres-Meja 2 , Carine Biessy 1 , Carolina Ortega-Olvera 2 , Ang elica Angeles-Llerenas 2 , Pietro Ferrari 1 , Eduardo Lazcano-Ponce 2 , and Isabelle Romieu 1 Abstract Background: w-3 polyunsaturatedfattyacids (PUFA) couldplaya protective role onthe riskof breast cancer; however, little is known about this relation among Mexican women. We evaluatedthe association between w-3 and w-6 PUFA intake and breast cancer risk by obesity status in Mexican women. Methods: Apopulation-based casecontrol study was conducted in Mexico, including 1,000 incident breast cancer cases and 1,074 controls matched to cases by age, health care system, and region. Women provided information on health and diet by in-person interview. Body mass index (BMI) measures were used to dene overall obesity. Obesity status was categorized as normal weight (18.5 < BMI < 25), overweight (25 BMI < 30), andobese (BMI 30). Aconditional logistic regressionmodel was usedtoassess the associationbetweenPUFA and breast cancer risk. Results: Overall, there was no signicant association between w-3 PUFA intake and breast cancer risk (P0.31). Anincreasedriskof breast cancer was associatedwithincreasingw-6 PUFAintake inpremenopausal women [OR 1.92, 95% condence interval (CI) 1.133.26; P 0.04]. A decreased risk of breast cancer was signicantly associated with increasing w-3 PUFA intake in obese women (OR 0.58, 95% CI 0.390.87; P 0.008) but not in normal weight nor in overweight women (P heterogeneity 0.017). Conclusions: Obesity status may affect the association between w-3 PUFAintake and breast cancer risk. The underlyingmechanisms maybe relatedtodecreasedinammationandimprovedadipokinandestrogenlevels induced by w-3 PUFA in adipose tissue in obese women. Impact: Increased intake of w-3 PUFA should be recommended among Mexican women in particular in obese women. Cancer Epidemiol Biomarkers Prev; 21(2); 31926. 2011 AACR. Introduction Breast cancer is the most frequent cancer among women with an estimated 1.38 million new cancer cases diagnosed in 2008 (23% of all cancers) and ranks second overall (10.9%of all cancers). It is now the most common cancer both in developed and developing regions with around 6,90,000 new cases estimated in each region (1). In Mexico, the estimated age-standardized incidence of breast cancer is 38.4 per 1,00,000 women (1). The increased incidence observed in Mexico during the last 20 years is linked in part to changes in the lifestyle of women, such as later age at rst pregnancy, decreasing duration of lactation, more sedentary lifestyle, and diet (2). Riskfactors relatedtodiet, obesity, andphysical activity are often blamed for increasing breast cancer rates. High fat intake, high carbohydrate intake, lowvegetable intake, and low soy intake have all been implicated, but the data are inconclusive (3). The role of fat intake in breast cancer etiology has been investigated for long but still remains one of the most controversial hypothesis in nutritional epidemiology (4). Experimental studies suggested strong tumor-enhancing effects of w-6 polyunsaturated fatty acids (PUFA) whereas protective effects of w-3 PUFA, present at high levels in sh oils, on mammary carcino- genesis, underlying the need to distinguish between the effects of w-6 and w-3 PUFA (5). Additional experimental studies suggest that high intakes of w-3 PUFAcould exert inhibitory effects on mammary tumorigenesis through competition with w-6 PUFA (6). Meta-analysis of epide- miologic studies reported a signicant increase in breast cancer risk with high saturated fat intake but failed to observe signicant association with total PUFA (7) or w-3 PUFA intakes (8). The hypothesis of a protective effect of Authors' Afliations: 1 Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France; and 2 Instituto Nacional de Salud P ublica, Centro de Investigaciones en Salud Poblacional, Cuernavaca, Morelos, M exico Corresponding Author: Isabelle Romieu, Nutrition and Metabolism, Inter- national Agency for Research on Cancer, 150, cours Albert Thomas, 69372 Lyon cedex 08, France. Phone: 33-0-472738094; Fax: 33-0-472738361; E-mail: romieui@iarc.fr doi: 10.1158/1055-9965.EPI-11-0896 2011 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention www.aacrjournals.org 319 on May 14, 2014. 2012 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst December 22, 2011; DOI: 10.1158/1055-9965.EPI-11-0896 w-3 PUFA on breast cancer risk deserves further consid- eration in epidemiologic studies. We analyzed the relationship of breast cancer risk to PUFA intake in a casecontrol study conducted in Mexico City. The analysis focused on w-3 PUFA intakes which have been hypothesized to encompass a potential for preventive strategies. In addition, we investigated how the associations between PUFA intakes and breast cancer risk are inuenced by obesity and menopausal status. Materials and Methods Study population A Multicenter study, population-based casecontrol study (CAMA) was conducted by the National Institute of Public Health in Cuernavaca, Mexico. Women were recruited between 2004 and2007 from3 regions in Mexico and their surrounding metropolitan areas: Mexico City, Monterrey, and Veracruz. Breast cancer cases (n 1,000) were women with newly diagnosed, histologically con- rmed in situ (n 20) or invasive breast cancer (n 980), as previously described (9). Cases received care from one of 12 participating hospi- tals from the 3 major health care systems in Mexico. The sample was, therefore, representative of the socioeconom- ic diversity of the general population of women living in these regions. Cases were excluded in the following situations: if they had received breast cancer treatment (radiotherapy, che- motherapy, or hormone therapy) in the past 6 months; if they currently used aromatase inhibitors (exemestane, letrozole, or anastrozole) or megestrol, a progesterone derivative; if they were pregnant; or if they were HIV positive. The study protocol and data collection were approvedby the Institutional ReviewBoardat the Nation- al Institute of Public Health andby equivalent committees at the collaborating hospitals. Controls (n 1,074) were frequency matched to the cases according to age, health care system, and region. They were selected on the basis of a probabilistic multi- stage design, withthe aimof sampling specic numbers of women in each 5-year category (range: 3569 years) based on the age distribution of cases reported by the Mexican Tumor Registry in 2002. Withinthe 3 study regions, one or more geographic regions (from Spanish,
Area Geoestad - tica Basica) were selected for sampling. Cases and controls provided written informed consent to participate in the study. Data collection Project nurses conducted in-person interviews among the cases, obtained anthropometric measures (height, weight, and waist and hip circumference), and collected blood samples. Among controls, interviewers adminis- tered an in-person household survey and scheduled an appointment for a hospital visit during which anthropo- metric measurements were obtained, mammographic screening was carried out, and a blood sample was taken. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Women were classied into different BMI categories according to the World Health Organization guidelines as follows: women with a BMI between 18.5 and 24.9 kg/m 2 had normal weight, women with a BMI between 25.0 and 29.9 kg/m 2 were considered overweight, and women with a BMI of 30.0 kg/m 2 or higher were classied as obese (10). Waist to hip ratio (WHR), as indicator of central obesity, was calculated as waist circumference (cm) divided by hip circumference (cm). The median value (0.91) was used as cutoff point. General health and lifestyle factors were addressed using a 243-itemquestionnaire. The questionnaire collect- ed information on lifetime alcohol consumption, socio- demographic characteristics, reproductive/hormonal factors (e.g., age at menarche and menopause, pregnan- cies, pregnancy outcomes, lactation history, use of oral contraceptives, and hormone therapy), family history of breast cancer, smoking history, and physical activity. To measure physical activity, participants were asked about the time spent sleeping and engaging in physical activity (light, moderate, and vigorous) over a usual week prior to the onset of symptoms. Cases were interviewed soon after diagnosis (median 3 days). Dietary information was obtainedby asking cases about their foodconsumptionthe year prior to the onset of the symptoms andtothe controls the year before the study started, using a separate 104-item semiquantitative food frequency questionnaire (FFQ) developed on the basis of consumption data from women living in Mexico City using methods described and already used (11). The relative validity compared with sixteen 24-hour recalls andreproducibilityof the FFQwas assessedin134 women in Mexico City (12). The procedures for secondary anal- yses of study data were approved by the Institutional Review Ofce at the Fred Hutchinson Cancer Research Center, Seattle, WA. PUFA exposure assessment For this specic study, w-6 and w-3 PUFA, and energy intakes were computed from FFQ by multiplying the average daily frequency consumption by the nutrient content of commonly used portion sizes. The nutrient database developed by the National Institute of Nutrition in Mexico (13) and the U.S. Department of Agriculture food composition tables (14) were used to calculate intakes. Exclusions Subjects withunrealistic total caloric intake (<500 Kcal/d and >5,000 Kcal/d) were excluded from the analysis (n 161). Twenty-three subjects were also excluded because of missing information on anthropometric values. The nal number of cases and controls involved in the statistical analyses are 914 (91.4%) cases and 976 (90.9%) controls. Chaj es et al. Cancer Epidemiol Biomarkers Prev; 21(2) February 2012 Cancer Epidemiology, Biomarkers & Prevention 320 on May 14, 2014. 2012 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst December 22, 2011; DOI: 10.1158/1055-9965.EPI-11-0896 Statistical analyses Baseline characteristics of the study population are compared by tertiles of w-3 PUFAintakes. For continuous variables, F tests were usedto test for signicance of linear trend by assigning ordinal scores to each successive cat- egory and treating variables as continuous in the regres- sion model. The CochranArmitage test for trend was used for categorical variables. ORs and 95% condence intervals (CI) for breast cancer risk in relation to w-6 and w-3 PUFAandto w-3 to w-6 PUFAratio were calculatedby conditional logistic regression (SAS statistical software, version 9, SAS Institute), stratied by the casecontrol set. PUFA were divided into tertiles on the basis of the dis- tribution among controls. Multivariate analyses were run controlling for potential confounders including BMI (con- tinuous), height, familyhistoryof breast cancer, age at rst menses, age at rst full-term pregnancy, number of full- term pregnancies, breast feeding, age at menopause, ever use of hormone for menopause, ever use of oral contraceptive, physical activity (expressed as METS units), socioeconomic status, energy intake (continuous), alcohol consumption (yes/no), and menopausal status. Linear trend tests were determined on the score variables (tertile categories). Subgroup analyses on the association between PUFA intakes and breast cancer risk were conducted by uncon- ditional logistic regression, including matching variables in the model, stratied by BMI (normal weight, 18.5 < BMI < 25; overweight, 25 BMI < 30; and obese, BMI 30), WHR (median value as cutoff point), and menopausal status (pre- and postmenopause). Tests for heterogeneity in the associations among PUFA levels and breast cancer risk were carried out using c 2 tests. Statistical tests were 2 sided and P values <0.05 were considered statistically signicant. Results Baseline characteristics of the study population by intakes of w-3 PUFA are presented in Table 1. Women in the highest tertile of w-3 PUFAhada higher energy intake, a higher w-6 PUFAintake, a higher alcohol consumption, a higher folate intake, and a higher vitamin E intake than women in the lowest tertile of w-3 PUFA intake (refer- ence). In the highest tertile of w-3 PUFA, the percentage of women in postmenopause was higher than those in pre- menopause. Women in the highest tertile of w-3 PUFA were more highly educated and of higher socioeconomic level than those in the lowest w-3 PUFA group. The associations between PUFA intake and breast can- cer risk in the overall population and stratied by men- opausal status are presented in Table 2. Overall, there was no signicant association between w-3 PUFA intake and breast cancer risk (P 0.31), whereas an increased risk of breast cancer was associated with increasing w-6 PUFA intake (P 0.04). Menopausal status did not change the risk estimate associated with w-3 PUFA. The increased risk associatedwith increasing w-6 PUFAintake appeared in premenopausal women (P 0.02) but not in postmen- opausal women (P 0.91). Finally, there was a trend for a decreased risk of breast cancer associated with a high w-3/w-6 PUFA ratio, particularly in premenopausal women (P 0.06). The associations between PUFA intake and breast can- cer risk stratied by BMI are presented in Fig. 1. A decreased risk of breast cancer was signicantly associ- ated with increasing w-3 PUFA intake in obese women (P 0.008; Fig. 1A) but not in overweight women (P 0.23; Fig. 1B) nor innormal weight (P0.54, P heterogeneity
0.017; Fig. 1C).
Similarly, a decreased risk of breast cancer was asso- ciated with increasing ratio of w-3 to w-6 PUFA in obese women (P 0.01), whereas no signicant associations were observed in normal weight (P 0.26) and in overweight women (P 0.40, P heterogeneity 0.05). Obesity status did not signicantly affect the positive association between breast cancer risk and w-6 PUFA intake (P heterogeneity 0.46) even though the positive association reached statistical signicance only in over- weight women (P 0.03). The same trend was observed between w-3 PUFA and breast cancer risk when stratifying by WHR but did not reach statistical signicance (P heterogeneity 0.23). Discussion This population-basedcasecontrol study conducted in Mexico reported an increased risk of breast cancer asso- ciated with increasing w-6 PUFA, particularly among premenopausal women. This study showed no clear evi- dence of an inverse association between estimated w-3 PUFA intake and breast cancer risk, in agreement with former meta-analyses of prospective studies (8). Howev- er, our studyprovidedsome indicationthat obesity status, denedby BMI measures, hadanimpact onrisk estimates for w-3 PUFA intake. A decreased risk of breast cancer associated with increasing w-3 PUFAintake was found in obese women, whereas no signicant inverse association was detected in normal weight and overweight women. Excessive amounts of w-6 PUFA, and a low ratio of w-3 to w-6 PUFA, as is found in todays Western diets, pro- mote the pathogenesis of many diseases, including breast cancer (15, 16). Because of the increased amounts of w-6 PUFA in the Western diet, the eicosanoid products from w-6 PUFA, specically prostaglandins, thromboxanes, leukotrienes, hydroxy fatty acids, and lipoxins, are formed in larger quantities than those formed from w-3 PUFA. The eicosanoids from w-6 PUFA are biologically active in very small amounts, and, if they are formed in large amounts, they contribute to the formation of inam- matory disorders and to proliferation of cells (16). Thus, the positive association between w-6 PUFA and breast cancer risk may be related to increased production of proinammatory products from w-6 PUFA. Overall, we found no inverse association between w-3 PUFA intake and breast cancer risk, in agreement with w-3 and w-6 Polyunsaturated Fatty Acids and Breast Cancer www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 21(2) February 2012 321 on May 14, 2014. 2012 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst December 22, 2011; DOI: 10.1158/1055-9965.EPI-11-0896 most epidemiologic studies based on estimated intakes (1719) or biomarkers (20, 21). As exceptions, inverse associations have been reported in Asian women having intakes up to 40 times greater than Western ones (2224). In the present study, w-3 PUFAintake was about 10 times lower than those reported in Western populations. In this context, clear inverse associations may not have been observed in our population study because w-3 PUFA intake might have been below the threshold for a protec- tive effect against breast cancer. A population-based prospective cohort study con- ducted among postmenopausal breast cancer women revealed that obesity status may inuence the association of breast cancer risk todietary factors (25). Our population study presented a wide range in BMI measures, allowing us to stratify on BMI, in contrast to other studies with a small range in BMI measures. We found that overall obesity status, as estimated by BMI measures, had an impact onriskestimates for w-3 PUFAintake. Adecreased risk of breast cancer was associated to increasing w-3 PUFA intake in obese women, whereas no signicant inverse association was detected in normal weight and overweight women. The same inverse trend between w-3 PUFA and breast cancer risk appeared in women accord- ing to WHR, as a measure of central adiposity, but did not reach statistical signicance. Table 1. Baseline characteristics of the study population by w-3 PUFA intakes Tertile of w-3 PUFA intake (median intake, g/d) Baseline characteristics 1 (0.016) 2 (0.04) 3 (0.08) P trend Age, y 52.3 (51.553.0) 50.0 (49.350.7) 49.9 (49.250.6) 0.31 BMI, kg/m 2 29.5 (29.129.9) 29.4 (29.029.8) 29.6 (29.230.0) 0.50 Normal weight (%) 14.5 16.1 16.1 0.45 Overweight (%) 42.9 41.6 38.4 0.10 Obese (%) 42.6 42.3 45.5 0.27 Menopausal status Premenopause (%) 37.4 45.9 45.3 Postmenopause (%) 62.6 54.1 54.7 0.004 Ever use oral contraceptives (%) 42.6 44.1 47.0 0.10 Ever use hormone therapy (%) 13.0 11.4 13.0 0.98 For postmenopausal only 16.8 19.1 20.9 0.13 Age at menarche, y 12.8 (12.712.9) 12.7 (12.612.8) 12.7 (12.612.8) 0.34 Combined age at rst birth and parity (%) 20 y (47%) 25 y (77.5%) 30 y (92.5%) Nulliparous 8.2 8.3 10.3 0.17 First birth before 30, 1 to 2 children 15.8 17.1 17.9 0.31 First birth before 30, 3 children 56.3 53.8 51.1 0.05 First birth at 30 19.7 20.8 20.8 0.63 Socioeconomic level (%) Lower 41.9 28.3 26.6 <0.0001 Middle 30.0 31.2 28.3 0.49 Upper 28.1 40.6 45.1 <0.0001 Education level (%), score (05)no primary/secondary 0 10.4 7.1 4.8 <0.0001 1 29.1 20.3 19.3 <0.0001 2 31.6 29.2 29.1 0.33 3 20.9 28.9 27.6 0.005 4 3.7 7.4 10.3 <0.0001 5 4.3 7.1 8.9 0.0009 Family history of breast cancer (%) 4.6 5.6 4.7 0.95 Physical activity, MET, h/wk 267.4 (264.0270.7) 271.9 (268.5275.3) 271.5 (268.1274.8) 0.39 Energy intake, kcal/d 1,740 (1,6951,785) 1,941 (1,8941,988) 2,176 (2,1242,228) 0.008 w-6 PUFA, g/d 3.34 (3.223.45) 4.09 (3.954.23) 4.94 (4.785.11) 0.013 w-3/w-6 ratio 0.00 (0.000.00) 0.01 (0.010.01) 0.02 (0.020.02) 0.035 Alcohol intake (%) No/yes 12.6 13.7 17.4 0.01 Folate intake, mg/d 266.1 (257.7274.9) 328.1 (317.8338.7) 399.2 (386.7412.1) 0.012 Vitamin E intake, mg/d 9.78 (9.4510.13) 11.18 (10.8111.57) 12.98 (12.5413.43) 0.020 Chaj es et al. Cancer Epidemiol Biomarkers Prev; 21(2) February 2012 Cancer Epidemiology, Biomarkers & Prevention 322 on May 14, 2014. 2012 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst December 22, 2011; DOI: 10.1158/1055-9965.EPI-11-0896 Differences in w-3-breast cancer risk association between obese and nonobese women might be related to the anti-inammatory effects of w-3 PUFA. Indeed, increased adiposity leads to a chronic inammation in adipose tissue, resulting in increased production of proinammatory cytokines (i.e., monocyte chemotactic protein-1, interleukin-6, TNF-a, plasminogen activator inhibitor-1; ref. 26). Obesity is also associated with high levels of insulin, a known mitogen. Experimental studies showedthat dietary supplementationwith w-3 PUFAwas associated with reduced adipose tissue inammation and increased insulin sensitivity in obese mice (27). In addition, preincubation of mammary tumor cells with proinammatory TNF-a stimulated uptake of w-3 PUFA comparedwithother fattyacids (28). Thus, w-3 PUFAmay have a protective effect on breast cancer risk in obese women which might be related to increased uptake of these fatty acids incells andsubsequent decreasedinam- mation andenhancedinsulin sensitivity in adipose tissue. Dysregulated adipokine secretion in obese subjects, particularly leptin and adiponectin (29), has been sus- pected to mediate the association of obesity with breast cancer (30). Growth of breast cancer cells could be regu- lated by various leptin-induced secondary messengers like STAT3, activator protein (AP-1), mitogen-activated protein kinase (MAPK), and extracellular signal-regulat- ed kinases (ERK), involved in aromatase expression, gen- eration of estrogens, and activation of estrogen receptor-a in malignant breast epithelium (31). Higher circulating levels of leptin found in obese subjects could be a growth- enhancing factor (as supportedby in vitro studies), where- as lower levels of adiponectin found in obese women may allowgrowth-promoting effects of leptin (31). Fish oil rich in w-3 PUFA has been shown to increase plasma levels of adiponectin in rodents and in human subjects and to decrease plasma leptin concentrations (26). The effect of w-3 PUFA on plasma levels of adipokins may be in part a result of activation of peroxisome proliferator-activated receptor g or inhibition of Toll-like receptor 4 (26). In this context, the possibility that w-3 PUFA led to decreased breast cancer risk in obese women as a result, at least in part, of improved adiponectin and leptin levels altered in obesity, should be considered. The discovery of the obesity-inammation-aromatase axis in the mammary gland and visceral fat may provide insight into mechanisms underlying the inverse associa- tion between w-3 PUFA and breast cancer risk in obese women. Elevated estrogen synthesis, as a consequence of increased aromatase expression in adipose tissue, is thought to be a growth factor associated with the obesity breast cancer risk association. Analysis of the stromal vascular and adipocyte fractions of the mammary gland suggested that macrophage-derived proinammatory mediators induced aromatase gene expression in obese mice (32). Aromatase expression in the breast has been shown to be upregulated by AMP-activated protein kinase and cyclic AMP responsive element binding pro- teinregulated transcription coactivator 2 in response to the altered adipokine milieu associated with obesity and may provide an important link between obesity and breast cancer risk (33). It is suggested that a high intake of w-3 PUFA relative to that of w-6 PUFA may decrease endogenous estrogen production via inhibition of aroma- tase activity/expression (34). However, no studies have yet directly addressed this issue in humans, and the potential of w-3 PUFA to inhibit aromatase activity/ expression altered in obesity needs to be investigated in the future. Table 2. ORs for breast cancer according to tertiles of PUFA intakes stratied by menopausal status Tertile of dietary PUFA PUFA 1 (referent) 2 OR (95% CI) 3 OR (95% CI) a P trend w-3 PUFA Overall population 1 0.91 (0.701.17) 0.87 (0.681.13) 0.31 Premenopausal women 1 0.78 (0.531.17) 0.80 (0.541.19) 0.18 Postmenopausal women 1 0.97 (0.691.36) 0.87 (0.611.22) 0.54 w-6 PUFA Overall population 1 1.32 (0.991.76) 1.45 (1.032.04) 0.04 Premenopausal women 1 1.65 (1.022.68) 1.92 (1.133.26) 0.02 Postmenopausal women 1 1.12 (0.771.63) 1.04 (0.651.68) 0.91 w-3/w-6 PUFA Overall 1 0.94 (0.741.20) 0.82 (0.641.05) 0.12 Premenopausal women 1 0.70 (0.491.01) 0.71 (0.481.03) 0.06 Postmenopausal women 1 1.26 (0.911.76) 0.89 (0.641.25) 0.56 a Adjusted for BMI (continuous), height, family history of breast cancer, age at rst menses, age at rst full-termpregnancy, number of full-termpregnancies, breast feeding, age at menopause, socioeconomic status, ever use of hormone for menopause, ever use of oral contraceptive, physical activity, energy intake (continuous), and alcohol consumption (yes/no). w-3 and w-6 Polyunsaturated Fatty Acids and Breast Cancer www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 21(2) February 2012 323 on May 14, 2014. 2012 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst December 22, 2011; DOI: 10.1158/1055-9965.EPI-11-0896 Stratifying on menopausal status did not modify the risk estimates for w-3 PUFA intake, but the positive association between w-6 PUFA intake and breast cancer risk, or the negative association between the ratio of w-3 to w-6 PUFA and breast cancer risk, observed overall was restrictedto the subgroupof premenopausal women. Few studies on the association between dietary fatty acids and breast cancer riskpresenteddata stratiedbymenopausal status. Inagreement withour ndings, one studyreported that the association between the ratio of w-3 to w-6 PUFA and breast cancer risk differed regarding to menopausal status, with a stronger association observed in the C -6 -3 -3/-6 1 2 3 1 2 3 1 2 3 55/117 119/178 174/180 112/134 110/156 126/185 148/149 105/164 95/162 1.00 1.17 1.05 1.00 0.77 0.58 1.00 0.72 0.61 0.731.87 0.611.81 0.511.15 0.390.87 0.491.07 0.420.90 PUFA 95% CI OR Cases/controls Tertiles 1 0.5 A -6 -3 -3/-6 1 2 3 1 2 3 1 2 3 66/123 136/129 196/127 117/137 134/126 147/116 147/141 137/125 114/113 1.00 1.47 1.86 1.00 1.08 1.28 1.00 1.25 1.18 0.942.30 1.073.23 0.731.60 0.861.91 0.851.83 0.791.75 PUFA B 95% CI OR Cases/controls Tertiles 2 1 -6 -3 -3/-6 1 2 3 1 2 3 1 2 3 26/31 62/44 76/44 46/33 52/46 66/40 55/39 66/44 43/36 1.00 1.37 1.27 1.00 0.54 0.54 1.00 1.23 0.62 0.543.45 0.423.86 0.221.35 0.231.30 0.582.60 0.271.39 PUFA 95% CI OR Cases/controls Tertiles 4 2 1 0.5 0.25 Figure 1. ORs for breast cancer according to tertile of PUFA intakes stratied by BMI. A, obese women; B, overweight women; C, normal weight women analyses on the association between PUFA intakes and breast cancer risk were conducted by unconditional logistic regression, including matching variables in the model, stratied by BMI (obese, BMI 30; overweight, 25 BMI < 30; and normal weight, 18.5 < BMI < 25). Chaj es et al. Cancer Epidemiol Biomarkers Prev; 21(2) February 2012 Cancer Epidemiology, Biomarkers & Prevention 324 on May 14, 2014. 2012 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst December 22, 2011; DOI: 10.1158/1055-9965.EPI-11-0896 subgroupof premenopausal womencomparedwith post- menopausal women (35). w-6 PUFA may have effects opposite to those of the w-3 series, and differences in breast cancer risk associated to w-6 PUFA between pre- and postmenopausal women may be related to plasma estrogenlevels, althoughthe relationshipbetweendietary PUFA and endogenous estrogen synthesis levels remains to be investigated in humans. There are some limitations inherent to the casecontrol design. Casecontrol studies of diet andcancer are subject to recall bias when ascertaining past dietary information. Recall bias can produce differential measurement error, whichcan unpredictably bias OR. These results needto be conrmedby biomarkers of PUFAintakes, as it is planned in this population study in the future. Conclusion The underlying mechanisms of the inverse associa- tion between w-3 PUFA intake and breast cancer risk among obese women is of particular interest for pre- vention strategies and warrant further investigation. In this context, experimental studies using models of obese rodents designed at investigating the potential of an enrichment of diet with w-3 PUFA to prevent or delay the appearance of chemically induced mammary tumors would give more support to our original obser- vation. Future studies of the relationship between w-3 PUFA intake and breast cancer risk should consider stratication on obesity status. Disclosure of Potential Conicts of Interest No potential conicts of interest were disclosed. Acknowledgments The authors thank all physicians responsible for the project in the different participating hospitals: Dr. German Castelazo (IMSS, Hospital de la Raza, Ciudad de Mexico, DF), Dr. Sinhue Barroso Bravo (IMSS, Hospital siglo XXI, Ciudad de Mexico, DF), Dr. Fernando Mainero Ratch- elous (IMSS, Hospital de Gineco-Obstetricia N0 4. "Luis Castelaco Ayala", Ciudad de Mexico, DF), Dr. Hernando Miranda Hernandez (SS, Hospital General de Mexico, Ciudad de Mexico, DF), Dr. Joaqu n Zarco Mendez (ISSSTE, Hospital 20 de Noviembre, Ciudad de Mexico, DF), Dr. Edelmiro Perez Rodr guez (Hospital Universitario, Monterrey, Nuevo Le on), Dr. Jes us Pablo Esparza Cano (IMSS, Hospital N0. 23 de Ginecolog a, Mon- terrey, Nuevo Le on), Dr. Heriberto Fabela (IMSS, Hospital N0. 23 de Ginecolog a, Monterrey, Nuevo Le on), Dr. Jose Pulido Rodr guez (SS, Hospital Metropolitano Dr "Bernardo Sepulveda", Monterrey, Nuevo Le on), Dr. Manuel de Jes us Garc a Solis (SS, Hospital Metropolitano Dr "Bernardo Sepulveda", Monterrey, Nuevo Le on), Dr. Fausto Hernandez Morales (ISSSTE, Hospital General, Veracruz, Veracruz), Dr. Pedro Cor- onel Brizio (SS, Centro Estatal de Cancerolog a "dr. Miguel Dorantes Mesa", Xalapa, Veracruz), Dr. Vicente A. Salda~ na Quiroz (IMSS, Hospital Gineco-Pediatr a N0. 71, Veracruz, Veracruz), and M.C. 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