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Carcinogenesis Advance Access originally published online on October 24, 2007
Carcinogenesis 2007 28(12):2548-2551; doi:10.1093/carcin/bgm211
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic polymorphisms in the apoptosis-associated genes FAS and FASL and breast cancer risk

Katherine D. Crew*, Marilie D. Gammon1, Mary Beth Terry2, Fang Fang Zhang3, Meenakshi Agrawal4, Sybil M. Eng5, Sharon K. Sagiv1, Susan L. Teitelbaum6, Alfred I. Neugut2 and Regina M. Santella4

Department of Medicine and the Herbert Irving Comprehensive Cancer Center, Columbia University, 161 Fort Washington Avenue, 10-1072, New York, NY 10032, USA
1 Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599-7435, USA
2 Department of Epidemiology, Columbia University, NY 10032, USA
3 Department of Epidemiology, University of North Texas Health Science Center at Fort Worth, TX 76107, USA
4 Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, NY 10032, USA
5 Global Epidemiology, Pfizer, NY 10017, USA
6 Department of Community and Preventive Medicine, Mount Sinai School of Medicine, NY 10029, USA

* To whom correspondence should be addressed. Tel: +1 212 305 1732; Fax: +1 212 305 0178; Email: kd59{at}columbia.edu


   Abstract
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FAS and FAS ligand (FASL) play key roles in apoptotic signaling and down-regulation of this pathway may facilitate tumorigenesis. Alterations in apoptosis genes may affect cancer risk by influencing individual susceptibility to environmental carcinogens. Using a population-based breast cancer case–control study on Long Island, New York, we examined whether polymorphisms in FAS and FASL modified the association between breast cancer risk and a marker of environmental exposures, polycyclic aromatic hydrocarbon (PAH)–DNA adducts. We examined polymorphisms in FAS (5' UTR –1377G/A and 5' UTR –670G/A) and FASL (5' UTR –844C/T) in 1053 breast cancer cases and 1102 population-based controls. There was no significant association between these genetic polymorphisms and breast cancer risk. The presence of at least one variant allele (GA or AA) in FAS1377 was associated with a 36% increase in breast cancer risk among those with detectable PAH–DNA adduct levels [odds ratio (OR) = 1.36, 95% confidence interval (CI) = 1.01–1.83]. In addition, lactation history significantly modified the association between FAS1377 and FAS670 genetic variants and breast cancer risk (OR = 1.46, 95% CI = 1.04–2.06 and OR = 1.71, 95% CI = 1.13–1.58, respectively, in those who ever lactated compared with those who did not with the wild-type alleles). Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in the FAS gene and detectable PAH–DNA adducts.

Abbreviations: CI, confidence interval; FASL, FAS ligand; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon


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The FAS receptor–ligand system plays a key role in apoptotic signaling in many cell types including cells of the immune system (1) and disruption of this pathway has been associated with tumorigenesis. FAS (CD95) belongs to the family of tumor necrosis factor receptors and binding by FAS ligand (FASL) triggers apoptosis mediated by cytotoxic T lymphocytes and natural killer cells. Various types of tumors express FASL, which may lead to resistance to apoptosis through the FAS pathway and evasion of the immune system (2,3). Germ line mutations within FAS have been shown to cause an autoimmune lymphoproliferative syndrome, which is associated with an increased risk of hematological malignancies (4). In addition, somatic mutations in the FAS and FASL genes have been detected in several cancers (5–8).

Single nucleotide polymorphisms in the promoter regions of FAS and FASL have been linked to the differential expression of these two genes. The FAS –1377A allele (G/A at position –1377 bp) and the FAS –670G allele (G/A at position –670 bp) disrupt Sp1 and STAT1 transcription factor binding, respectively, which results in decreased FAS gene expression (9–11). The FASL –844C allele (C/T at position –844 bp) creates a binding site for the CAAT/enhancer-binding protein β transcription factor, resulting in higher basal FASL gene expression (12). These polymorphisms have been linked to an increased risk of acute myeloid leukemia (10), lung cancer (13), esophageal cancer (14), colorectal cancer (15), cervical cancer (16–18) and breast cancer (19,20). Significant interactions were found between these polymorphisms and tobacco smoking (14,21,22), alcohol consumption (23,24) and estrogen exposure (25) on cancer risk.

There is no report on either FAS or FASL in relation to breast cancer risk and environmental exposures. In this study, we genotyped FAS and FASL for these polymorphisms in 1053 cases with incident breast cancer and 1102 population-based controls to test the hypothesis that they are associated with the risk of breast cancer. We also investigated the potential role of polymorphisms in FAS and FASL genes and polycyclic aromatic hydrocarbon (PAH)–DNA adduct levels, tobacco use, alcohol consumption and estrogen exposure.


   Materials and methods
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 Introduction
 Materials and methods
Results
 Discussion
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Study population
The Long Island Breast Cancer Study Project is a large population-based case–control study conducted in Long Island, New York (26). Briefly, cases comprised women >20 years of age who were residents of Nassau and Suffolk counties, spoke English and were newly diagnosed with in situ or invasive breast cancer between 1 August 1996 and 31 July 1997. Controls were identified by random digit dialing (under age 65) and rosters from the Center for Medicare and Medicaid Services (65 or older) and frequency matched to the expected age distribution of cases by 5 year age groups. In-person interviews were completed for 1508 (82.1%) cases and 1556 (62.8%) controls. Blood samples were collected from 1102 (73.1%) cases and 1141 (73.3%) controls who completed the main interview. Of those who donated a blood sample, we were unable to genotype 4.4% of the cases and 3.4% of controls, mainly due to lack of sufficient DNA to complete the assay. Thus, our final sample size was 1053 cases and 1102 controls.

Genotyping assay
DNA was isolated (27) and genotyping for FAS (–1377G/A, rs2234767 and –670G/A, rs1800682) and FASL (–844C/T, rs763110) was conducted using the Taqman 5'-Nuclease Assay (Applied Biosystems, Foster City, CA). The consistency rate of quality control samples was 100% for FAS –1377G/A, 94% for FAS –670G/A and 96% for FASL –844C/T.

Exposure data
Exposure information came from the parent study questionnaire (26), which was administered by trained interviewers in the subject's home, and laboratory analyses using the DNA samples to measure PAH–DNA adducts (27). PAH–DNA adduct levels were assessed among 873 cases and 941 controls using a competitive enzyme-linked immunosorbent assay with a polyclonal antiserum generated against benzo(a)pyrene diol epoxide-modified DNA, but which recognized the diol epoxide adducts of several other PAHs, as described previously (28).

Statistical methods
Unconditional logistic regression models were used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) after adjusting for potential confounding variables (29). All models were adjusted for age at reference (defined as age at diagnosis for cases and age at identification for controls). We examined potential confounding by the following factors: race, first-degree family history of breast cancer, history of benign breast disease, age at menarche, age at first pregnancy, parity, fertility problems, menopausal status, oral contraceptives, hormone replacement therapy, body mass index, lifetime alcohol intake and cigarette smoking status. Confounders were included in the final model if their inclusion changed the exposure estimate by >10% (29). None of these covariates confounded the estimates on exposure by >10%.

PAH–DNA adducts were categorized as non-detectable/detectable and into quartiles based on the distribution of detectable adducts among controls. Stratified analyses were used to evaluate whether FAS and FASL genotype effects were modified by estrogen-related factors (menopausal status, age at menarche, age at first pregnancy, parity, lactation history, oral contraceptive and hormone replacement therapy use), PAH–DNA adduct levels, cigarette smoking and alcohol consumption.


   Results
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The frequencies of the FAS –1377G/A, FAS –670G/A and FASL –844C/T variant alleles were 0.13, 0.47 and 0.43, respectively, among the controls and were not statistically different from the cases (data not shown). The genotype distributions among both cases and controls did not differ from the predicted distribution under Hardy–Weinberg equilibrium. Risk of breast cancer did not differ statistically by the FAS and FASL genotypes overall (Table I).


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  		Table I. Genotype frequency for polymorphisms in apoptosis genes, Long Island Breast Cancer Study Project, 1996–1997

 
Age-adjusted estimates stratified by lactation history are presented in Table II. An increase in breast cancer risk was seen among those with a positive lactation history and at least one variant allele (GA or AA) for FAS1377 or homozygous variant for FAS670 (AA) (OR = 1.46, 95% CI = 1.04–2.06 and OR = 1.71, 95% CI = 1.13–2.58, respectively). However, no association was seen between FAS genotype and other estrogen-related factors, such as age at menarche, age at first pregnancy, parity, oral contraceptive and hormone replacement therapy use (data not shown).


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  		Table II. Age-adjusted ORs and 95% CIs for polymorphisms in FAS gene stratified by lactation history, Long Island Breast Cancer Study Project, 1996–1997

 
The age-adjusted analyses of FAS genotypes and breast cancer risk stratified by PAH–DNA adduct levels are presented in Table III. The presence of at least one variant allele in FAS1377 (GA or AA) was associated with a 36% increase in risk of breast cancer among those with detectable DNA adducts (OR = 1.36, 95% CI = 1.01–1.83). However, the multiplicative interaction term was not statistically significant (P = 0.20). When subjects with detectable adducts were further quartiled for consideration of a possible dose response, associations were of borderline significance only for the fourth quartile: OR = 1.60 (1.00–2.57) for those with the FAS1377 GA or AA genotype and OR = 1.77 (95% CI = 0.99–3.15) for those with FAS670 AA genotype. We found no association between FASL genotype, PAH–DNA adducts and breast cancer risk. Analyses for association based on smoking status and alcohol consumption were not statistically significant for either FAS or FASL polymorphism (data not shown).


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  		Table III. Age-adjusted ORs and 95% CIs for polymorphisms in FAS gene stratified by PAH–DNA adducts, Long Island Breast Cancer Study Project, 1996–1997

 

   Discussion
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 Materials and methods
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We found that there was no statistically significant association between the risk for breast cancer and genotypes at FAS –1377G/A, FAS –670G/A and FASL –844C/T. However, FAS genotype significantly modified the associations between PAH–DNA adducts and lactation history and breast cancer risk. This is the first report of FAS and FASL genotypes in relation to breast cancer risk and environmental exposures.

Down-regulation of FAS-mediated apoptosis can prolong the normal cellular lifespan, allowing cells to acquire mutations and facilitating tumorigenesis. Decreased expression of FAS or increased expression of FASL favors malignant transformation and progression (30). Down-regulation of FAS and aberrant expression of FASL has been reported in many cancers (5–8). In addition, germ line mutations in FAS are associated with cancer susceptibility (4,31).

Single nucleotide polymorphisms in the promoter region of FAS (–1377G/A and –670G/A) and FASL (–844C/T) have been shown to alter the transcriptional activity of these genes (11,12). The –1377G/A and –670G/A polymorphisms in FAS occur within transcription binding sites for Sp1 and STAT1, respectively (9). The promoter of FASL has a single nucleotide polymorphism at –844C/T that is located in a binding motif for the CAAT/enhancer-binding protein β transcription factor. Basal FASL expression is higher in cells carrying the C allele compared with the T allele, as measured in a luciferase reporter assay in the peripheral blood fibrocytes (12). Increased risks for acute myeloid leukemia (10), lung cancer (13), esophageal cancer (14), colorectal cancer (15), cervical cancer (16–18) and breast cancer (19,20) have been associated with these polymorphisms in FAS and FASL. Significant interactions were found between these polymorphisms and tobacco smoking and esophageal cancer risk (14). FASL expression can be induced by tobacco smoking (21,22) and alcohol consumption (23,24). We did not find any statistically significant associations between these genotypes and breast cancer risk by smoking status or alcohol consumption.

We found a significant association between FAS1377 and FAS670 genotype and breast cancer risk among those with a positive lactation history. Estrogen is known to stimulate cell proliferation and breast cancer cell growth. Paradoxically, high doses of estrogen can promote tumor regression in post-menopausal women with hormone-dependent breast cancer, but the mechanism is unknown (32,33). In vitro studies show that high doses of estradiol can decrease cell growth and increase apoptosis in breast cancer cells (34). The apoptotic action of estrogen is thought to be mediated by the FAS/FASL system. Mor et al. (35) demonstrated that FASL in breast tissue is functionally active and that estrogen regulates its expression. They identified a putative estrogen receptor response element in the promoter region of the FASL gene. Estrogen has also been shown to trigger T-cell apoptosis by up-regulating FAS and FASL in cancer cells (25). Estrogen activation of FAS-mediated apoptosis may explain the relationship we observed between FAS genotype, lactation history and breast cancer risk. However, we did not find an association between FAS or FASL genotype and other estrogen-related factors.

We found a significant association between FAS1377 genotype and breast cancer risk among those with detectable PAH–DNA adducts. PAHs are ubiquitous in the environment and may be derived from exposure to combustion products of fossil fuels, cigarette smoking and dietary intake of grilled and smoked foods (36). PAHs are potent mammary carcinogens in experimental animals (37). Previous epidemiologic studies (38,39) noted that increased levels of aromatic DNA adducts in breast tissue were associated with breast cancer risk. The Long Island Breast Cancer Study Project was undertaken specifically to investigate environmental factors including the role of PAH–DNA adducts in breast cancer and reported an overall association of 1.32, 95% CI = 1.00–1.74 for detectable versus non-detectable adducts (27), a finding that was validated when we analyzed all samples available in the Long Island Breast Cancer Study Project (40). However, the association between adduct levels and breast cancer risk did not vary when stratified by two of the main sources of PAHs among non-occupationally exposed populations, namely cigarette smoking and consumption of grilled and smoked foods (40). Among controls, we did observe a modest increase in PAH–DNA adducts in current and former cigarette smokers (OR = 1.50, 95% CI = 1.00–2.24; OR = 1.46, 95% CI = 1.05–2.02, respectively) (41). These findings suggest that the body's metabolic response to this carcinogenic exposure, rather than exposure level, may be more relevant in breast carcinogenesis.

In a case–control study of Chinese women, Zhang et al. (19) recently reported that genetic polymorphisms in FAS (–1377G>A and –670G>A) and FASL (–844C>T) were associated with a moderately increased risk of breast cancer. In addition, the FASL –844CC genotype was associated with increased activation-induced cell death of T cells ex vivo and higher apoptotic tumor-infiltrating lymphocytes in breast tumor tissue. Krippl et al. (20) described a case–control study of 500 breast cancer patients and 500 controls in a Caucasian population in Austria and found a significant association between FAS –1377A and increased risk of breast cancer, but null associations with FAS –670G/A and FASL –844C/T. We observed no significant associations between risk for breast cancer and polymorphisms in FAS and FASL. However, FAS –1377G/A genotype significantly modified the association between PAH–DNA adducts and breast cancer risk. The reason for these inconsistencies may reflect differences in genetic background or gene–environment interactions between the study populations.

This case–control study is one of the largest evaluations of genetic variants in apoptosis-associated genes and breast cancer risk. Potential sources of bias in our study design include subject selection, recall bias and measurement error. Response rates were lower among controls compared with cases, especially among women over the age of 75 years (26). We cannot exclude the possibility that these genotypes may be related to breast cancer risk in an older population; however, the null association was not modified by menopausal status. Although blood donation rates were reasonably high among study respondents (>70%), blood donors differed from those who did not donate blood on a number of factors (26). However, all models included the frequency matching factor age at reference, and adjustment for other known breast cancer risk factors did not appreciably change the effect estimates, and were therefore not included in our final models. Recall bias may have occurred if respondents differentially recalled exposure information on estrogen-related factors, alcohol intake and cigarette use, but not PAH–DNA adducts because it was not based on self-report. Such misclassification could result in a bias away from the null for putative risk factors. However, it is unlikely that such misclassification would differ by genotype status and therefore is unlikely to explain the patterns we observed. Measurement error is limited in this study because of the very high reliability (94–100%) in the measurement of genotype. The measurement of DNA adducts in mononuclear cells, including lymphocytes, has been demonstrated to be a valid surrogate marker for estimating the burden of at least one type of DNA adduct in the breast (42). Unlike questionnaire exposure data, measurement of PAH–DNA adduct levels is not subject to recall bias, although laboratory error is possible. However, this measurement error in PAH–DNA adduct levels is unlikely to differ by genotype status.

Particular strengths of our study include the population-based design, the measurement of PAH–DNA adduct levels and the large sample size that facilitated examination of modifying effects. In summary, we found that the specific FAS and FASL polymorphisms determined here are not likely to play an important independent role in breast cancer susceptibility. However, FAS genotype modified the associations between PAH–DNA adducts and lactation history and risk of breast cancer.


   Funding
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 Abstract
 Introduction
 Materials and methods
 Results
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 Funding
References
 
National Cancer Institute and the National Institute of Environmental Health Sciences (U01 CA/ES66572, P30ES09089 and P30ES10126); Breast Cancer Research Foundation Award.


   Acknowledgments
 
The authors acknowledged gifts from private citizens.

Conflict of Interest Statement: None declared.


   References
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 References
 

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Received June 26, 2007; revised August 16, 2007; accepted September 12, 2007.


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