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Cancer Epidemiology Biomarkers & Prevention Vol. 13, 1480-1484, September 2004
© 2004 American Association for Cancer Research

Dietary Intake of Conjugated Linoleic Acids and Risk of Premenopausal and Postmenopausal Breast Cancer, Western New York Exposures and Breast Cancer Study (WEB Study)

Susan E. McCann1, Clement Ip2, Margot M. Ip3, Michelle K. McGuire5, Paola Muti6, Stephen B. Edge4, Maurizio Trevisan6 and Jo L. Freudenheim6

Departments of 1 Epidemiology and 2 Chemoprevention, Division of Cancer Prevention and Population Sciences, 3 Pharmacology and Therapeutics, and 4 Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York; 5 Department of Food Science and Human Nutrition, Washington State University, Pullman, Washington; and 6 Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York

Requests for reprints: Susan E. McCann, Department of Epidemiology, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8842; Fax: 716-845-8487. E-mail: susan.mccann{at}roswellpark.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Specific fatty acids may have differential effects on breast cancer etiology. Animal studies have suggested that conjugated linoleic acids (CLA), a group of fatty acids found predominantly in dairy products and the meat of ruminants, have potent anticarcinogenic properties. We examined breast cancer risk and dietary CLA intake among 1,122 women with primary, incident, histologically confirmed breast cancer and 2,036 controls frequency matched to cases by age, race, and county of residence. Diet was assessed with a self-administered 104-item food frequency questionnaire and other relevant data were collected by detailed in-person interviews. We examined risk with intake of total CLAs and the 9c,11t-18:2 isomer of CLA (9,11 CLA). Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression, adjusting for age, the residual of fat adjusted for energy, and other breast cancer risk factors. No association was observed between intakes of total CLA or 9,11 CLA and overall risk of premenopausal or postmenopausal breast cancer. We observed little association between CLA intakes and risk of estrogen receptor (ER)–negative or ER-positive tumors, although, compared with premenopausal women in the lowest quartile of 9,11 CLA intake, those in the highest quartile had a marginally significant reduction in risk of having an ER-negative tumor (odds ratio, 0.40; 95% confidence interval, 0.16–1.01). Our findings suggest that, although CLA intake was not related to overall breast cancer risk, there may be associations with tumor biology at least among premenopausal women.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Dietary fat intake has long been the focus of etiologic studies in breast cancer epidemiology. In general, although ecologic and case-control studies have suggested increased risks associated with higher total dietary fat intakes, cohort studies and meta-analyses have concluded that high total dietary fat intake is not related to an increased risk of breast cancer (1, 2). However, fat consists of many different fatty acids with differential physiologic activities. Whereas total fat intake has been inconsistently related to breast cancer, it is plausible that the composition of dietary fat may affect risk (3, 4).

Conjugated linoleic acids (CLA) are naturally occurring fatty acids found in dairy products and the meat of ruminants, which have been shown to possess anticarcinogenic properties (5, 6). Many isomers of CLA exist and are formed in the rumen of ruminants as intermediates in the hydrogenation of linoleic acid to vaccenic acid (9t-18:1); however, 9c,11t-18:2 (9,11 CLA) accounts for at least 90% of the available isomers (7). The protective effect of CLA against mammary carcinogenesis in vivo, and its ability to inhibit growth of breast cancer cells in vitro, has been consistently shown in animal and in vitro studies (8-14).

Human studies of CLA and breast cancer have been limited; furthermore, to our knowledge, none has been conducted in the United States. No association with risk was observed in a study investigating CLA content in breast adipose tissue and breast cancer (15). Two studies have investigated dietary intake of CLA and postmenopausal breast cancer; one showed a weak, positive association (16) and the other showed a 60% reduction in risk associated with higher intakes (17). No studies to date have included an examination of tumor characteristics; although previous studies do not strongly support an overall protective effect by CLA, tumor biology might be affected. Therefore, we investigated the impact of dietary CLA intake in association with risk of premenopausal and postmenopausal breast cancer as well as the impact of CLA on tumor estrogen receptor (ER) status in the Western New York Exposures and Breast Cancer Study (WEB Study).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Data were collected as part of a large case-control study of breast cancer and dietary and environmental exposures, the WEB Study, conducted between 1996 and 2001. The study protocol was approved by the institutional review boards of the University at Buffalo and participating hospitals, and informed consent was obtained from all subjects.

Cases included 1,166 women ages 35 to 79 years with incident, primary, histologically confirmed breast cancer identified by nurse case finders in the participating hospitals in Erie and Niagara counties. Population-based controls (n = 2,105) were frequency matched by age, race, and county of residence to cases. Women ages <65 years were randomly selected from the New York State Department of Motor Vehicles drivers' license list and those ages ≥65 years were randomly selected from the Health Care Financing Administration Medicare rolls. Of the women for whom we could determine eligibility, 72% of the cases and 65% of the controls agreed to participate in the study. We were unable to determine eligibility for 18% of identified cases and 45% of identified controls. The primary reasons for not determining eligibility was illness in the cases and inability to contact or refusals among the controls. The present analyses are limited to the 1,122 cases and 2,036 controls with complete dietary data.

Data on demographics, smoking history, reproductive history, and other study variables were collected by trained interviewers during in-person computer-assisted interviews. Height and weight were measured by trained technicians using a standardized protocol. Body mass index was calculated as weight (kg) divided by the square of height (m). Clinical characteristics of tumors from women with breast cancer (e.g., tumor grade and stage and ER status) were obtained from chart review by trained nurses. ER status was defined according to hospital-specific protocols, and in general, a tumor was classified as ER positive by a positive result from the ER binding assay or at least 5% ER-positive cells by immunohistochemical assay.

Dietary intake in the year 12 to 24 months prior to the interview was collected using a self-administered modified version of the Health Habits and History food frequency questionnaire developed by researchers at the National Cancer Institute (18). Dietary intakes of total CLA and 9,11 CLA were calculated from food composition data compiled at Washington State University (Pullman, WA; ref. 19). CLA intakes were expressed as daily consumption.

Statistical Analyses
All analyses were conducted using SAS for Windows version 8.0. Analyses were stratified by menopausal status. A woman was considered postmenopausal if any of the following conditions were true: her menses had ceased permanently and naturally; she had had a hysterectomy and was >50 years; her menses had ceased permanently due to radiation or other medical treatment and she was >55 years; she was taking hormone replacement therapy and she was >55 years; she had had a bilateral oophorectomy; or her menses had not ceased permanently or not sure or do not know and never took hormones and she was >55 years.

Descriptive statistics for demographic, personal, and reproductive characteristics of cases and controls were compared using Student's t test for continuous variables and {chi}2 for categorical variables. Differences between cases and controls in CLA and 9,11 CLA were assessed with generalized linear models adjusting for total fat intake. To estimate risk associated with CLA intake, the continuous variables (CLA and 9,11 CLA) were categorized into quartiles based on the intake distributions of the controls. Odds ratios (OR) and 95% confidence intervals (95% CI) for each quartile referent to the lowest quartile of intake were computed with unconditional logistic regression adjusting for age, education, age at menarche, parity, age at first birth, history of benign breast disease, family history of breast cancer, and the residual of total fat adjusted for total energy. Models for the postmenopausal women were further adjusted for age at menopause. The residual of fat was calculated from the regression of total energy on total fat and represents the effect of total fat independent of total calories. Because of the strong correlation of fat with energy (r = 0.91), this analytic strategy allows for control of potential confounding due to differences in the composition of fat intake independent of the contribution by fat to energy intake. We tested additional models (nondietary risk factors + energy; nondietary risk factors + total fat) with little effect on the point estimates; however, inclusion of the residual of total fat produced the tightest 95% CIs. We used polytomous logistic regression adjusting for the same covariates included in the overall risk estimates to simultaneously estimate risks of ER-positive and ER-negative breast cancer compared with all controls.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Participants in the WEB Study were predominantly Caucasian (Table 1). Among premenopausal women, compared with controls, cases were slightly older (44.8 versus 44.0 years; P < 0.01), more likely to report a history of benign breast disease (36.3% versus 20.9%; P < 0.01), and more likely to report a family history of breast cancer (18.5% versus 10.4%; P < 0.01). No differences were observed between premenopausal cases and controls for education, age at menarche, parity, age at first birth, or body mass index. Among postmenopausal women, compared with controls, cases had more years of education (13.4 versus 13.0 years; P < 0.01), had younger age at menarche (12.6 versus 12.7 years; P < 0.05), had lower parity (2.5 versus 3.0; P < 0.01), had younger age at first birth (19.5 versus 21.1 years; P < 0.05), had later age at menopause (48.3 versus 47.4 years; P < 0.01), were more likely to report a history of benign breast disease (33.0% versus 22.7%; P < 0.01), and more likely to report a family history of breast cancer (19.4% versus 12.5%; P < 0.01). For the dietary variables examined, no differences were observed between premenopausal and postmenopausal women for total dairy, milk, or cheese intakes; total meat or red meat intakes; or total dietary fat intakes (premenopausal women only); however, total saturated fat intakes were higher in cases compared with controls for both premenopausal and postmenopausal women (25.3 versus 23.4 g/d; P < 0.05 for premenopausal women and 21.9 versus 20.3 g/d; P < 0.01 for postmenopausal women). Finally, premenopausal cases compared with controls had slightly lower total CLA and 9,11 CLA intakes, whereas postmenopausal cases compared with controls tended to have slightly higher intakes of total CLA and 9,11 CLA (Table 1).


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  		Table 1. Descriptive characteristics of breast cancer cases and controls, WEB Study

 
For analyses of overall risk and risk of ER-negative or ER-positive breast cancer associated with CLA or 9,11 CLA intakes, we present both crude and fully adjusted ORs. As we observed clear evidence of confounding due to the nondietary risk factors, our results and discussion will focus on the fully adjusted risk estimates. We observed no association with dietary intake of total CLA or 9,11 CLA and either premenopausal or postmenopausal breast cancer in these data (Table 2). However, among premenopausal women, those in the highest quartile of 9,11 CLA intake compared with the lowest quartile had marginally significant reduced risks of having an ER-negative tumor (adjusted OR, 0.40; 95% CI, 0.16–1.01 for ER-negative breast cancer cases compared with controls; Table 3). There were few differences in risk by ER status among postmenopausal women by intake of either total CLA or 9,11 CLA (Table 3).


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  		Table 2. ORs and 95% CIs for risk of breast cancer associated with total CLAs and 9,11 CLA, WEB Study

 

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  		Table 3. ORs and 95% CIs for risk of breast cancer associated with intakes of CLA by tumor ER status, WEB Study

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The relationship between dietary fat intake and breast cancer has been somewhat controversial. In general, prospective studies investigating total fat intake and breast cancer have suggested no association (1, 2). However, dietary fat consists of several fatty acids, which may have differential effects on cancer etiology. In animal models, CLAs have been shown to exert strong anticarcinogenic activities (8-14), although the limited human epidemiologic data have been less convincing (15-17).

Our data do not support a strong association of CLA intake with overall risk of premenopausal or postmenopausal breast cancer. Several factors may have contributed to our findings. First, although the CLA intakes observed in our study are comparable with those reported in other human studies, the levels of intake are much lower than those used in animal studies. In a study by Ip et al. (8), a significant inhibition of mammary carcinogenesis (35% decrease in risk) was observed in rats consuming 12 mg/d of CLA. This corresponds to a human equivalent of ~2.8 g/d of CLA for a 70 kg person. The mean daily intake of CLA in the present data ranged between 134 and 161 mg/d with an upper limit of <1 g/d. The usual consumption of CLA may be below the levels necessary to produce a risk-lowering effect.

On the other hand, CLA intake may have been underestimated. Although we used a comprehensive food frequency questionnaire that contained the majority of food sources for CLA, these instruments have been shown to underestimate CLA intake when compared with food duplicate methodology and food records (19). However, food frequency questionnaires estimate usual intake over a defined time period, whereas food duplicate methodology and food records measure actual intake over a short defined time period. In fact, in epidemiologic studies, ranking of participants on relative intake is more important than estimation of actual intake. Furthermore, whereas we underestimated usual intake, the amount of underestimation suggested by Ritzenthaler et al. (19) would still result in levels well below those used in animal studies (8).

Finally, we queried usual dietary intake in the year 12 to 24 months before diagnosis. The major sources of CLA include dairy products and consumption of dairy products tends to be fairly stable throughout adulthood. Nevertheless, dietary intake during adulthood may not be the appropriate time period of interest. Recent studies have suggested that adolescent diet may be more relevant in the etiology of breast cancer (20, 21). Furthermore, animal experiments support this hypothesis by showing that CLA administration prior to and during puberty reduces 7,12-dimethylbenz(a)anthracene–induced or N-nitroso-N-methylurea–induced mammary carcinogenesis (22).

Interestingly, although we observed little association of CLA intake with overall risk in this study, we did observe marginally significant reduced risks of ER-negative breast cancer among premenopausal women in the highest quartile of 9,11 CLA intake. This finding suggests that CLA, especially the 9,11 isomer, which is the predominant isomer in foods, may affect tumor biology even if it has little effect on overall breast cancer development. This is especially notable given that the observed reduction in risks of ER-negative tumors were among the premenopausal women, suggesting that the effect occurred during a relatively short time period (i.e., immediately prior to or during tumor development). A possible mechanism for this finding could be that dietary CLA affects the ER content of the mammary epithelium and subsequently that of the tumors that develop from that epithelium. If CLA affects the proportion of mammary epithelial cells that express ER, specifically by increasing the ratio of ER-positive to ER-negative cells, there would be a decreased likelihood that the cell from which a tumor develops would be ER negative. Higher CLA intakes could have important implications for reducing the burden of breast cancer by retarding the development of a less prognostically favorable tumor. Further research into the mechanisms for these findings is warranted.

In conclusion, we found that, although higher intakes of total CLA and 9,11 CLA do not seem to be related to overall breast cancer risk, risks of ER-negative breast cancer among premenopausal women were reduced. Our study adds to the limited literature concerning dietary CLA intake and human breast cancer. It also raises questions about the relevant time period for effects as well as what level of intakes are important. Additional research is necessary to address these issues.


   Footnotes
 
Grant support: National Cancer Institute grant CA89123-01A1, U.S. Army Medical Research and Material Command grant DAMD17-96-1-6202, and NIH grant R01 CA92040.

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 2/ 2/04; revised 4/ 1/04; accepted 4/ 6/04.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation