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
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
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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
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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
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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
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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. Teresa Shamah
Levy, INSP, Cuernavaca Mor.
Grant Support
This work was supported by Consejo Nacional de Ciencia y Tecnologia
CONACYT and the NIH.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
this fact.
Received September 20, 2011; revised November 18, 2011; accepted
December 2, 2011; published OnlineFirst December 22, 2011.
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