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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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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

AbstractBackground: w -3polyunsaturatedfattyacids (PUFA)couldplaya protective role on theriskof breastcancer;

however, little is known about this relation among Mexican women.We evaluatedthe association between w -3and w -6 PUFA intake and breast cancer risk by obesity status in Mexican women.

Methods: A population-based casecontrol studywas conducted in Mexico, including 1,000 incident breastcancer cases and 1,074 controls matched to cases by age, health care system, and region. Women providedinformation on health and diet by in-person interview. Body mass index (BMI) measures were used to deneoverall obesity. Obesity statuswas categorized as normal weight (18.5 < BMI < 25),overweight(25 BMI < 30),andobese (BMI 30).A conditionallogistic regression modelwas usedto assess theassociationbetweenPUFAand breast cancer risk.

Results: Overall, there was no signicant association between w -3 PUFA intake and breast cancer risk(P 0.31). Anincreasedrisk of breast cancer wasassociated withincreasing w -6 PUFAintake in premenopausalwomen [OR 1.92, 95% condence interval (CI) 1.133.26; P 0.04]. A decreased risk of breast cancer wassignicantly 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 ( Pheterogeneity 0.017).

Conclusions: Obesity status may affect the associationbetween w -3 PUFA intake andbreast cancerrisk.Theunderlyingmechanisms maybe related to decreasedinammation andimprovedadipokin andestrogenlevelsinduced 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 inobese women. Cancer Epidemiol Biomarkers Prev; 21(2); 31926. 2011 AACR.

Introduction

Breast cancer is the most frequent cancer amongwomen with an estimated 1.38 million new cancer casesdiagnosed in 2008 (23% of all cancers) and ranks secondoverall(10.9% of all cancers). It is now the most commoncancer both in developed and developing regions witharound 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). Theincreased incidence observed in Mexico during the last20 years is linked in part to changes in the lifestyle of

women, such as later age at rst pregnancy, decreasingduration of lactation, more sedentary lifestyle, anddiet (2).

Riskfactors relatedto diet, obesity,and physicalactivityare often blamed for increasing breast cancer rates. Highfat intake,highcarbohydrate intake, lowvegetable intake,and low soy intake have all been implicated, but the dataare inconclusive (3). The role of fat intake in breast canceretiology has been investigated for long but still remainsone of the most controversial hypothesis in nutritionalepidemiology (4). Experimental studies suggested strongtumor-enhancing effects of w -6 polyunsaturated fattyacids (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 theeffects of w -6 and w -3 PUFA (5). Additional experimentalstudies suggest thathigh intakes of w -3 PUFA could exertinhibitory effects on mammary tumorigenesis throughcompetition with w -6 PUFA (6). Meta-analysis of epide-miologic studies reported a signicant increase in breastcancer risk with high saturated fat intake but failed toobserve signicant association with total PUFA (7) or w -3PUFA intakes (8). The hypothesis of a protective effect of

Authors' Af liations: 1 Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France; and 2 Instituto Nacional de SaludPublica, Centro de Investigaciones en Salud Poblacional, Cuernavaca,Morelos, M exico

Corresponding Author: Isabelle Romieu, Nutritionand Metabolism, Inter-nationalAgencyfor Research onCancer, 150, cours Albert Thomas, 69372Lyon cedex 08, France. Phone: 33-0-472738094; Fax: 33-0-472738361;E-mail: [email protected]

doi: 10.1158/1055-9965.EPI-11-0896

2011 American Association for Cancer Research.

Cancer Epidemiology,

Biomarkers& Prevention

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w -3 PUFA on breast cancer risk deserves further consid-eration in epidemiologic studies.

We analyzed the relationship of breast cancer risk toPUFA intake in a casecontrol study conducted in

Mexico City. The analysis focused on w -3 PUFA intakeswhich have been hypothesized to encompass a potentialfor preventive strategies. In addition, we investigatedhow the associations between PUFA intakes and breastcancer risk are inuenced by obesity and menopausalstatus.

Materials and Methods

Study populationA Multicenter study, population-based casecontrol

study (CAMA) was conducted by the National Instituteof Public Health in Cuernavaca, Mexico. Women wererecruitedbetween 2004 and2007from 3 regions in Mexicoand 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. Thesamplewas, therefore, representative of thesocioeconom-ic diversity of the general population of women living inthese regions.

Cases were excluded in the following situations: if theyhad 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 progesteronederivative; if they were pregnant; or if they were HIVpositive. The study protocol and data collection wereapprovedby theInstitutionalReviewBoard at theNation-al Instituteof PublicHealth and by equivalentcommitteesat the collaborating hospitals.

Controls ( n 1,074) were frequency matched to thecases according to age, health care system, and region.They were selected on the basis of a probabilistic multi-stagedesign,with theaimof samplingspecicnumbers of women in each 5-yearcategory (range: 3569 years)basedon the age distribution of cases reported by the MexicanTumorRegistryin 2002. Within the3 study regions, oneormore 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 collectionProject 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 anappointment for a hospital visit during which anthropo-metric measurements were obtained, mammographic

screening was carried out, anda blood sample was taken.Body mass index (BMI) was calculated as weight (kg)divided by height (m) squared. Women were classiedinto different BMI categories according to the World

Health Organization guidelines as follows: women witha 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 wereconsidered overweight, and women with a BMI of 30.0 kg/m 2 or higher were classied as obese (10). Waistto hip ratio (WHR), as indicator of central obesity, wascalculated as waist circumference (cm) divided by hipcircumference (cm). The median value (0.91) was used ascutoff point.

General health and lifestyle factors were addressedusing a 243-itemquestionnaire. The questionnaire collect-ed information on lifetime alcohol consumption, socio-demographic characteristics, reproductive/hormonalfactors (e.g., age at menarche and menopause, pregnan-cies, pregnancy outcomes, lactation history, use of oralcontraceptives, and hormone therapy), family history of breast cancer, smoking history, and physical activity. Tomeasure physical activity, participants were asked aboutthe time spent sleeping and engaging in physical activity(light, moderate, andvigorous) over a usual week prior tothe onset of symptoms.

Cases were interviewed soon after diagnosis (median3 days). Dietary informationwasobtainedby asking casesabouttheirfoodconsumption theyearprior tothe onsetof thesymptomsand tothe controlstheyear beforethestudystarted, using a separate 104-item semiquantitative foodfrequency questionnaire (FFQ) developed on the basis of consumption data from women living in Mexico Cityusing methods described and already used (11). Therelative validity compared with sixteen 24-hour recallsandreproducibilityof theFFQwas assessedin 134womenin Mexico City (12). The procedures for secondary anal-yses of study data were approved by the InstitutionalReview Ofce at the Fred Hutchinson Cancer ResearchCenter, Seattle, WA.

PUFA exposure assessment For this specic study, w -6 and w -3 PUFA, and energy

intakes were computed from FFQ by multiplying theaverage daily frequency consumption by the nutrientcontent of commonly used portion sizes. The nutrientdatabase developed by the National Instituteof Nutritionin Mexico (13) and the U.S. Department of Agriculturefood composition tables (14) were used to calculate

intakes.

ExclusionsSubjectswithunrealistictotal caloric intake( 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 thestatistical analyses are 914 (91.4%) cases and 976 (90.9%)controls.

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Statistical analysesBaseline characteristics of the study population are

compared by tertilesof w -3 PUFAintakes.For continuousvariables, F testswereused totest forsignicance 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 wasused for categorical variables. ORs and 95% condenceintervals (CI) for breast cancer risk in relation to w -6 andw -3PUFAandto w -3to w -6PUFAratiowerecalculatedbyconditional logistic regression (SAS statistical software,version 9, SAS Institute), stratiedby the casecontrolset.PUFA were divided into tertiles on the basis of the dis-tribution among controls. Multivariate analyses were runcontrolling for potential confounders including BMI(con-tinuous), height,familyhistoryofbreast cancer,age atrstmenses, 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 oralcontraceptive, physical activity (expressed as METSunits), 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 PUFAintakes and breast cancer risk were conducted by uncon-ditional logistic regression, including matching variablesin themodel, stratiedby BMI(normal weight, 18.5 < BMI< 25; overweight, 25 BMI < 30; and obese, BMI 30),WHR (median value as cutoff point), and menopausalstatus (pre- and postmenopause). Tests for heterogeneityin the associations among PUFA levels and breast cancerrisk were carried out using c 2 tests. Statistical tests were 2sided and P values

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most epidemiologic studies based on estimated intakes(1719) or biomarkers (20, 21). As exceptions, inverseassociations have been reported in Asian women having

intakes up to 40 times greater than Western ones (2224).In thepresent study, w -3 PUFAintakewas about 10 timeslower than those reported in Western populations. In thiscontext, clear inverse associations may not have beenobserved in our population study because w -3 PUFAintake 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 womenrevealed that obesity status may inuence the association

ofbreast cancer riskto dietary factors (25).Our populationstudy presented a wide range in BMI measures, allowingus to stratify on BMI, in contrast to other studies with a

small range in BMI measures. We found that overallobesity status, as estimated by BMI measures, had animpacton riskestimates for w -3PUFAintake.A decreasedrisk of breast cancer was associated to increasing w -3PUFA intake in obese women, whereas no signicantinverse association was detected in normal weight andoverweight women. The same inverse trend between w -3PUFA and breast cancer risk appeared in women accord-ingto WHR, as a measure of central adiposity, butdid notreach 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 (51.5 53.0) 50.0 (49.3 50.7) 49.9 (49.2 50.6) 0.31BMI, kg/m 2 29.5 (29.1 29.9) 29.4 (29.0 29.8) 29.6 (29.2 30.0) 0.50Normal weight (%) 14.5 16.1 16.1 0.45Overweight (%) 42.9 41.6 38.4 0.10Obese (%) 42.6 42.3 45.5 0.27Menopausal status

Premenopause (%) 37.4 45.9 45.3Postmenopause (%) 62.6 54.1 54.7 0.004

Ever use oral contraceptives (%) 42.6 44.1 47.0 0.10Ever use hormone therapy (%) 13.0 11.4 13.0 0.98For postmenopausal only 16.8 19.1 20.9 0.13 Age at menarche, y 12.8 (12.7 12.9) 12.7 (12.6 12.8) 12.7 (12.6 12.8) 0.34Combined age at rst birth and parity (%) 20 y (47%) 25 y (77.5%) 30 y (92.5%)

Nulliparous 8.2 8.3 10.3 0.17First birth before 30, 1 to 2 children 15.8 17.1 17.9 0.31First birth before 30, 3 children 56.3 53.8 51.1 0.05First birth at 30 19.7 20.8 20.8 0.63Socioeconomic level (%)

Lower 41.9 28.3 26.6

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Differences in w -3-breast cancer risk association between obese and nonobese women might be related tothe anti-inammatory effects of w -3 PUFA. Indeed,increased adiposity leads to a chronic inammationin adipose tissue, resulting in increased production of proinammatory cytokines (i.e., monocyte chemotacticprotein-1, interleukin-6, TNF- a , plasminogen activatorinhibitor-1; ref. 26). Obesity is also associated with highlevels of insulin, a known mitogen. Experimental studiesshowed thatdietarysupplementationwith w -3PUFA wasassociated with reduced adipose tissue inammationand increased insulin sensitivity in obese mice (27). Inaddition, preincubation of mammary tumor cells withproinammatory TNF- a stimulated uptake of w -3 PUFAcompared withother fatty acids (28).Thus, w -3PUFAmayhave a protective effect on breast cancer risk in obesewomen which might be related to increased uptake of these fatty acids in cells andsubsequent decreased inam-mationand enhancedinsulinsensitivity 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 breastcancer (30). Growth of breast cancer cells could be regu-lated by various leptin-induced secondary messengers

like STAT3, activator protein (AP-1), mitogen-activatedprotein kinase (MAPK), and extracellular signal-regulat-ed kinases (ERK), involved in aromatase expression, gen-erationof estrogens, and activation of estrogenreceptor- ain malignant breast epithelium (31). Higher circulatinglevels of leptin found in obesesubjects could be a growth-enhancing factor (as supported by invitro studies),where-as lowerlevels of adiponectin found in obese women mayallow growth-promoting effects of leptin (31).Fishoil richin w -3 PUFA has been shown to increase plasma levels of

adiponectin in rodents and in human subjects and todecrease plasma leptin concentrations (26). The effect of w -3 PUFA on plasma levels of adipokins may be in part aresult of activation of peroxisome proliferator-activatedreceptor g or inhibition of Toll-like receptor 4 (26). In thiscontext, the possibility that w -3 PUFA led to decreased breast cancer risk in obese women as a result, at least inpart, of improved adiponectin and leptin levels altered inobesity, should be considered.

The discovery of the obesity-inammation-aromataseaxis in the mammary gland and visceral fat may provideinsight into mechanisms underlying the inverse associa-tion between w -3 PUFA and breast cancer risk in obesewomen. Elevated estrogen synthesis, as a consequenceof increased aromatase expression in adipose tissue, isthought to be a growthfactor associated with theobesity breast cancer risk association. Analysis of the stromalvascular and adipocyte fractions of the mammary glandsuggested that macrophage-derived proinammatorymediators induced aromatase gene expression in obesemice (32). Aromatase expression in the breast has beenshown to be upregulated by AMP-activated proteinkinase and cyclic AMP responsive element binding pro-teinregulated transcription coactivator 2 in response to

the altered adipokine milieu associated with obesity andmay provide an important link between obesity and breast cancer risk (33). It is suggested that a high intakeof w -3 PUFA relative to that of w -6 PUFA may decreaseendogenous estrogen production via inhibition of aroma-tase activity/expression (34). However, no studies haveyet directly addressed this issue in humans, and thepotential of w -3 PUFA to inhibit aromatase activity/expression altered in obesity needs to be investigated inthe future.

Table 2. ORs for breast cancer according to tertiles of PUFA intakes strati ed 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 (0.70 1.17) 0.87 (0.68 1.13) 0.31Premenopausal women 1 0.78 (0.53 1.17) 0.80 (0.54 1.19) 0.18Postmenopausal women 1 0.97 (0.69 1.36) 0.87 (0.61 1.22) 0.54

w -6 PUFA Overall population 1 1.32 (0.99 1.76) 1.45 (1.03 2.04) 0.04Premenopausal women 1 1.65 (1.02 2.68) 1.92 (1.13 3.26) 0.02Postmenopausal women 1 1.12 (0.77 1.63) 1.04 (0.65 1.68) 0.91

w -3/ w -6 PUFA Overall 1 0.94 (0.74 1.20) 0.82 (0.64 1.05) 0.12Premenopausal women 1 0.70 (0.49 1.01) 0.71 (0.48 1.03) 0.06Postmenopausal women 1 1.26 (0.91 1.76) 0.89 (0.64 1.25) 0.56

a Adjusted for BMI (continuous), height, family history of breast cancer, age at rst menses, age at rst full-term pregnancy, number of full-termpregnancies,breastfeeding, ageat menopause, socioeconomic status, ever useof hormonefor menopause, ever useof oralcontraceptive, physical activity, energy intake (continuous), and alcohol consumption (yes/no).

w -3 and w -6 Polyunsaturated Fatty Acids and Breast Cancer

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Stratifying on menopausal status did not modify therisk estimates for w -3 PUFA intake, but the positiveassociation between w -6 PUFA intake and breast cancerrisk, or thenegative association between theratio of w -3tow -6 PUFA and breast cancer risk, observed overall wasrestricted to thesubgroupof premenopausal women. Few

studies on the association between dietary fattyacids and breast cancerrisk presenteddata stratiedby menopausalstatus.In agreement withour ndings,one study reportedthat the association between the ratio of w -3 to w -6 PUFAand breast cancer risk differed regarding to menopausalstatus, with a stronger association observed in the

C

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Figure 1. ORs for breast cancer according to tertile of PUFA intakes strati ed by BMI. A, obese women; B, overweight women; C, normal weight womenanalyses onthe association between PUFAintakesand breast cancerrisk wereconducted by unconditionallogistic regression, includingmatching variablesin the model, strati ed by BMI (obese, BMI 30; overweight, 25 BMI < 30; and normal weight, 18.5 < BMI < 25).

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subgroupof premenopausal women compared withpost-menopausal women (35). w -6 PUFA may have effectsopposite 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 plasmaestrogenlevels,although therelationshipbetween dietaryPUFA and endogenous estrogen synthesis levels remainsto be investigated in humans.

There are some limitations inherent to the casecontroldesign. Casecontrolstudiesof dietandcancer are subjectto recall bias when ascertaining past dietary information.Recall bias can produce differential measurement error,whichcanunpredictably bias OR. These results need tobeconrmed by biomarkers ofPUFAintakes, as itis plannedin this population study in the future.

Conclusion

The underlying mechanisms of the inverse associa-tion between w -3 PUFA intake and breast cancer riskamong obese women is of particular interest for pre-vention strategies and warrant further investigation. Inthis context, experimental studies using models of obeserodents designed at investigating the potential of anenrichment of diet with w -3 PUFA to prevent or delaythe appearance of chemically induced mammarytumors would give more support to our original obser-vation. Future studies of the relationship between w -3PUFA intake and breast cancer risk should considerstratication on obesity status.

Disclosure of Potential Con icts of Interest

No potential conicts of interest were disclosed.

Acknowledgments

The authors thank all physicians responsible for the project in thedifferent participating hospitals: Dr. Germ an Castelazo (IMSS, Hospitalde la Raza, Ciudad de M exico, DF), Dr. Sinhu e Barroso Bravo (IMSS,Hospital siglo XXI, Ciudad de M exico, DF), Dr. Fernando Mainero Ratch-elous (IMSS, Hospital de Gineco-Obstetricia N0 4. "Luis Castelaco Ayala",Ciudad de M exico, DF), Dr. Hernando Miranda Hern andez (SS, HospitalGeneral de M exico, Ciudad de M exico, DF), Dr. Joaqu n Zarco M endez(ISSSTE, Hospital 20de Noviembre, Ciudadde M exico,DF), Dr.EdelmiroPerez Rodrguez (Hospital Universitario, Monterrey, Nuevo Le on), Dr. Jesus Pablo Esparza Cano (IMSS, Hospital N0. 23 de Ginecolog a, Mon-terrey, Nuevo Le on), Dr. Heriberto Fabela (IMSS, Hospital N0. 23 deGinecolog a, Monterrey, Nuevo Le on), Dr. Jos e Pulido Rodr guez (SS,Hospital Metropolitano Dr "Bernardo Sepulveda", Monterrey, NuevoLeon), Dr. Manuel de Jes us Garc a Solis (SS, Hospital Metropolitano Dr"Bernardo Sepulveda", Monterrey, Nuevo Le on), Dr. Fausto Hern andezMorales (ISSSTE, Hospital General, Veracruz, Veracruz), Dr. Pedro Cor-onel Brizio (SS, Centro Estatal de Cancerolog a "dr. Miguel DorantesMesa", Xalapa, Veracruz), Dr. Vicente A. Salda

~

na Quiroz (IMSS, HospitalGineco-Pediatr a N0. 71, Veracruz, Veracruz), and M.C. Teresa ShamahLevy, INSP, Cuernavaca Mor.

Grant Support

This work wassupported by Consejo Nacional deCiencia y TecnologiaCONACYT and the NIH.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.

Received September 20, 2011; revised November 18, 2011; acceptedDecember 2, 2011; published OnlineFirst December 22, 2011.

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