Polymorphisms in angiotensin II type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore

Woon-Puay Koh*, Jian-Min Yuan1, David Van Den Berg1, Hin-Peng Lee and Mimi C. Yu1

Department of Community, Occupational and Family Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Singapore and 1 USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033-0800, USA

* To whom correspondence should be addressed. Tel: +65 6874 4975; Fax: +65 6779 1489; Email: cofkwp{at}nus.edu.sg


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Angiotensin II is converted from its precursor by angiotensin I-converting enzyme (ACE) and has been shown to mediate growth in breast cancer cell lines via ligand-induced activity through the angiotensin II type 1 receptor (AGTR1). Earlier we showed that women with the low activity genotype of the ACE gene have a statistically significantly (~50%) reduced breast cancer risk compared with those possessing the high activity ACE genotype. To further test the hypothesis that angiotensin II participates in breast carcinogenesis through AGTR1, we examined genetic polymorphisms in the 5'-region of the AGTR1 gene (A-168G, C-535T and T-825A) in relation to risk of breast cancer in 258 breast cancer cases and 670 female controls within the Singapore Chinese Health Study. Relative to the homozygotes, individual genotypes with one or two copies of the respective allelic variants (putative low risk genotypes) were each associated with an ~30% reduction in risk of breast cancer. Risk of breast cancer decreased with increasing number of low risk AGTR1 genotypes after adjustment for potential confounders. Relative to those carrying no low risk genotypes (homozygous for A, C and T alleles for the three polymorphisms, respectively), the odds ratios (95% confidence intervals) were 0.84 (0.51–1.37) for women possessing one low risk genotype and 0.68 (0.46–1.01) for women possessing two or three low risk genotypes (P for trend = 0.05). When both AGTR1 and ACE gene polymorphisms were examined simultaneously, women possessing at least one AGTR1 low risk genotype in combination with the ACE low activity genotype had an odds ratio of 0.35 (95% confidence interval, 0.20–0.62) compared with those possessing the ACE high activity genotype and no AGTR1 low risk genotype. Our findings suggest that pharmacological inhibition of the angiotensin II effect by blockade of ACE and/or AGTR1 could be potential targets for the prevention and treatment of breast cancer.

Abbreviations: ACE, angiotensin I-converting enzyme; AGTR1, angiotensin II type 1 receptor; AGTR2, angiotensin II type 2 receptor; CI, confidence interval; LD, linkage disequilibrium; OR, odds ratio


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Angiotensin II is converted from its precursor by the catalytic action of angiotensin I-converting enzyme (ACE) and plays an important role in circulatory homeostasis. There is a growing body of experimental evidence that angiotensin II exerts pro-mitotic, pro-proliferative and angiogenic effects (15) and the administration of ACE inhibitors reduces tumor growth in animal models of cancer (6,7), thus suggesting a role for angiotensin II in cancer etiology or progression. Angiotensin II mediates its complex physiological effects by binding to two pharmacologically distinct receptors, angiotensin II type 1 receptor (AGTR1) and angiotensin II type 2 receptor (AGTR2) (8). The two receptors share only ~32% structural homology and appear to couple with their effectors via different intracellular pathways (9). The two receptors are thought to mediate opposing effects and the overall effect of angiotensin II is dependent on a balance of expression and effects of these two receptors. The stimulatory actions of angiotensin II on angiogenesis, cell growth and cell proliferation in tissues are mediated via AGTR1 (10,11) and opposed via AGTR2 (12,13). While AGTR1 is found in a wide variety of normal tissues, increased expression is often found in the corresponding neoplastic tissues, suggesting that its overexpression is involved in carcinogenesis (14,15). In relation to breast cancer, AGTR1 is expressed in human breast cells and up-regulated in benign and neoplastic breast tissues (16). AGTR1 stimulates proliferation of human breast cancer cells in vitro and the effect is blocked by losartan, the prototype AGTR1 antagonist (17).

In epidemiological studies users of ACE inhibitors exhibited a reduced risk of cancer when compared with general population rates in a cohort of hypertensive patients in west Scotland, the reduction in cancer risk being most prominent for female breast cancer (18). Furthermore, we have examined the relationship between ACE gene polymorphisms and breast cancer risk in a population-based, prospective cohort of Chinese women in Singapore (The Singapore Chinese Health Study) and demonstrated that individuals carrying genotypes which predisposed them to lower plasma concentrations of this enzyme had a significantly reduced breast cancer risk, by ~50%, independent of other environmental and familial risk factors for the disease (19).

Subsequent to our findings, Haiman et al. examined the two ACE gene polymorphisms in relation to breast cancer risk among African-American, Japanese, Latina and non-Hispanic white women in the Hawaii/Los Angeles Multiethnic Cohort Study and observed no significant association for the A-240T gene polymorphism [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.86–1.34] and a marginal increase in risk for the I/D gene polymorphism (OR 1.21, 95% CI 1.01–1.45), thus yielding seemingly conflicting results (20). To further elucidate the effect of angiotensin II on the development of breast cancer in humans, we examined whether genetic polymorphisms in the promoter region of the AGTR1 gene were associated with breast cancer risk among female participants in The Singapore Chinese Health Study. In the present study we included three genetic polymorphisms (A-168G, C-535T and T-825A) of the AGTR1 gene that have been shown to be associated with cardiovascular disease risk and, thus, are likely to be functional (2123). The results of the present study could help to clarify whether the angiotensin II system is indeed involved in human breast carcinogenesis. If we could establish an association between AGTR1 genotype and breast cancer risk, we would be providing further evidence that regulation of angiotensin II, either through its production or effects on the receptor, can affect breast cancer development.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
The subjects were participants in The Singapore Chinese Health Study, a population-based, prospective investigation of diet and cancer risk. From April 1993 to December 1998 a total of 63 257 Chinese women and men aged 45–74 years enrolled in the study (only women are included in this report) (24). We restricted study subjects to the two major dialect groups of Chinese in Singapore, Hokkien and Cantonese. The subjects were residents of government housing estates; 86% of the Singapore population reside in these facilities. At recruitment, a face-to-face interview was conducted in the subject's home by a trained interviewer, using a structured questionnaire which requested information on demographics, lifetime use of tobacco, menstrual and reproductive history (women only), medical history and family history of cancer. The questionnaire also included a dietary component assessing current intake patterns (including questions about coffee, tea and alcoholic beverages), which was subsequently validated against a series of 24 h diet recalls (24).

Between April 1994 and July 1999 we attempted to collect blood and single void urine specimens from a random 3% sample of study enrollees. Details of the biospecimen collection, processing and storage procedures have been described previously (19). If the subject refused to donate blood, he/she was asked to donate buccal cells. Out of 1059 female cohort participants contacted for biospecimen donation, blood (n = 514) or buccal cells (n = 164) were collected from 678 subjects, representing a participation rate of 64%. The control group for the present study comprised the 670 women who remained free of breast cancer as of April 30, 2002.

We identified incident breast cancer cases through the population-based cancer registry in Singapore (25). As of 30 April 2002, 399 cases of incident breast cancer had developed among female cohort subjects. Histological and staging information for all breast cancer diagnoses were confirmed by manual review of the pathology reports and clinical charts. Blood (n = 198) or buccal (n = 60) specimens were available for 258 (65%) of the breast cancer cases. Breast cancer cases who did not give a blood or buccal cell sample were less educated than those who provided such a sample (44 versus 30% had no formal education). Slightly more Cantonese gave biospecimens (69%) compared with Hokkiens (60%). The two groups were otherwise similar with respect to age at cancer diagnosis (mean 61 versus 59 years).

Informed consent forms were completed by all participants at baseline interview and time of collection of blood (or buccal cells) and urine specimens. The Institutional Review Boards at the University of Southern California and the National University of Singapore approved this study.

Genotyping methods
DNA was purified from buffy coats of peripheral blood and buccal cell samples using a PureGene Blood Kit (Gentra Systems, Minneapolis, MN) or a QIAamp 96 DNA Blood Kit (Qiagen, Valencia, CA). Genotyping assays were developed for the three AGTR1 promoter polymorphisms using the fluorogenic 5'-nuclease assay (TaqMan Assay) (26). The TaqMan assays were performed using a TaqMan PCR Core Reagent Kit (Applied Biosystems, Foster City, CA) according to the manufacturer's instructions. The oligonucleotide primers (Integrated DNA Technology, Coralville, IA) for amplification of the polymorphic regions of AGTR1 and the fluorogenic oligonucleotide probes (Applied Biosystems) used to detect each of the alleles are listed in Table I. PCR amplification using ~10 ng genomic DNA was performed in a thermal cycler (MWG Biotech, High Point, NC) with an initial step of 95°C for 10 min, followed by 50 cycles of 95°C for 25 s and 1 min at the annealing temperature. The fluorescence profile of each well was measured in an ABI 7900HT Sequence Detection System and the results analyzed with Sequence Detection Software (Applied Biosystems). Experimental samples were compared with 12 controls to identify the three genotypes at each locus. Any samples that were outside the parameters defined by the controls were identified as non-informative and were retested.


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Table I. Primers and probes used for genotyping the AGTR1 gene polymorphisms

 
Statistical analysis
We examined linkage disequilibrium (LD) among the three gene polymorphisms in control subjects using the Expectation–Maximization algorithm (27). The measure of the statistical association for LD (R2), a better measure for LD than the commonly used Lewontin's D, was used to assess the correlation of alleles at two sites (28). We used standard methods for unmatched case–control studies to examine the effects of the AGTR1 gene polymorphisms on breast cancer risk (29). The strength of a given gene–cancer association was measured by the OR and corresponding 95% CI and two-sided P value. P values <0.05 were considered statistically significant. Statistical analysis was carried out using the SAS software version 9.1 (SAS Institute, Cary, NC).

For the AGTR1 gene polymorphisms the AG/GG, TC/TT and TA/AA genotypes were grouped, due to the relative rarity of the GG, TT and AA genotypes. We examined the sum of ‘low risk’ genotypes in relation to risk, under the assumption that all three polymorphisms were functional and that their effects on breast cancer risk were additive. In addition to age at recruitment, year of recruitment and dialect group (Cantonese or Hokkien), level of education (none, primary, secondary school or higher), age (year) when periods became regular (<12, 13–14, 15–16, 17+ and those whose periods never became regular) and number of live births (none, 1–2, 3–4 or 5+) were included as covariates in all regression models.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 258 breast cases and 670 controls were included in this case–control study. The mean age of cases at the time of diagnosis was 59.1 ± 7.5 years, with a range of 46–78 years. Table II shows the distribution of selected characteristics of breast cancer cases and controls in the study population. The cases and controls were similar in distribution by dialect group. Since the cases were better educated than the controls, all subsequent case–control analyses were adjusted for level of education. Cases had significantly earlier age at menarche, fewer numbers of live births and later age at menopause compared with controls. More cases were nulliparous or had their first live birth at a later age compared with controls. Most cases (91.9%) and controls (94.2%) had never used replacement hormone therapy.


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Table II. Distribution of known risk factors for breast cancer in Singapore Chinese women (The Singapore Chinese Health Study)

 
The genotypic distributions of all three polymorphisms, A-168G, C-535T and T-825A, of the ATGR1 gene were in Hardy–Weinberg equilibrium (all P values >0.30). R2 for the correlation of alleles at two sites (i.e. for LD) was 0.73 between the A-168G and T-825A polymorphisms, 0.57 between the T-825A and C-535T polymorphisms and 0.43 between the A-168G and C-535T polymorphisms (all P values <0.0001). The frequencies of the minor alleles of the three polymorphisms among control subjects were 0.094, 0.187 and 0.119, respectively. Their genotype frequencies were presented in Table III.


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Table III. AGTR1 genotypes in relation to breast cancer risk (The Singapore Chinese Health Study)

 
Table III shows the distribution of AGTR1 genotypes in relation to breast cancer risk among study subjects. For each gene polymorphism women with one or two copies of the allelic G, T or A variants showed a reduced risk of breast cancer compared with those with the homozygous AA, CC or TT genotypes. Thus, the AG/GG, CT/TT and TA/AA genotypes were considered putative low risk genotypes for breast cancer. We further examined breast cancer risk according to the number of putative low risk genotypes in a subject. We noted that risk of breast cancer decreased with increasing number of low risk AGTR1 genotypes after adjustment for potential confounders (Table III) (P for trend = 0.053).

Table IV shows the distribution of the combined genotypes of the AGTR1 and ACE gene polymorphisms. The genotypic polymorphisms of the two genes were not correlated; the contingency coefficient was 0.05 (P = 0.23) in controls and 0.005 (P = 0.94) in cases. Compared with women with a combination of the high activity genotype for the ACE gene polymorphism and a zero low risk genotype for the AGTR1 gene polymorphism, women possessing either the low activity genotype for the ACE gene polymorphism or at least one low activity genotype for the AGTR1 gene polymorphism have an ~40–50% reduction in breast cancer risk. For women possessing a combination of both an ACE low activity genotype as well as one or more AGTR1 low risk genotypes, their breast cancer risk was reduced by 65% (OR 0.35, 95% CI 0.20–0.62).


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Table IV. Combined ACE and AGTR1 genotypes in relation to breast cancer risk (The Singapore Chinese Health Study)

 
We repeated our analysis stratified by subjects' menopausal status at baseline. The associations between the AGTR1 and ACE gene polymorphisms and breast cancer risk were present in both groups of women, albeit seemingly stronger in post- versus pre-menopausal women at baseline (data not shown). However, the association between the ATGR1 and ACE genotype and breast cancer risk was not statistically significantly different between the post- and pre-menopausal women (P = 0.57). Since AGTR1 antagonists may be prescribed to patients with hypertension and ACE inhibitors to patients with hypertension, heart disease or diabetes, the usage of such drugs among our study subjects may potentially confound the gene–cancer associations under study. Therefore, we repeated the analysis after excluding all subjects with a history of hypertension, heart disease or diabetes. Compared with the results based on all study subjects, the genotype–cancer associations remained essentially unchanged (data not shown).


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study is an extension of our previous study that showed a reduced risk of breast cancer among individuals with the low activity genotypes of the ACE and is a first report of an association between AGTR1 gene polymorphisms and breast cancer risk.

Recent experimental data support the hypothesis that a lower expression or activity of AGTR1 is linked to reduced breast cancer risk. Angiotensin II has been demonstrated to stimulate proliferation in a human breast adenocarcinoma cell line via AGTR1 and this growth effect may be involved in the pathogenesis of premalignant lesions (11). AGTR1 activation by angiotensin II also exerted a proliferative effect via the Na+/K+ ATPase pathway in a breast cancer cell line and this action was blocked by the drug losartan, an AGTR1 antagonist. Blockade of AGTR2 did not produce a similar effect (17). Hence, ligand-induced activation of AGTR1 by angiotensin II may exert neoplastic and angiogenic effects on breast tissues and thus increase breast cancer risk. This present study provides epidemiological data that lend support to these prior experimental data. More importantly, it complements our previous study that showed that ACE activity/level is associated with breast cancer risk and, therefore, further strengthens our hypothesis that angiotensin II is etiologically linked to breast carcinogenesis.

Contrary to our earlier report, Haiman et al. did not observe any significant reduction in breast cancer risk in women possessing the AT/AA or ID/II genotypes in the Hawaii/Los Angeles Multiethnic Cohort Study (20). Unlike the Hawaii/Los Angeles Multiethnic Cohort Study, subjects in The Singapore Chinese Health Study are genetically homogeneous, since they are full-blooded descendents of immigrants from two contiguous prefectures in southern China. It is well recognized that the effect of a given gene on disease risk could be diluted or masked in racially mixed populations (30,31), an unavoidable limitation to more or less degrees in all US-based studies. In addition, diet-derived compounds such as long chain polyunsaturated fatty acids and tea polyphenols have been shown to modulate the production or effects of angiotensin II on the cardiovascular system (32,33). Therefore, it is plausible that dietary and other lifestyle factors can exert an influence on the effect of angiotensin II on breast carcinogenesis. We have shown a distinct difference in the diet, including intake of long chain polyunsaturated fatty acids and tea polyphenols, between Singapore Chinese and US whites and non-whites (24). Thus, differences in the prevalence of dietary and other environmental cofactors between the Singapore Chinese and US populations may explain, at least in part, the disparate findings between the two large-scale cohorts. We intend to fully examine dietary factors, including intake of polyunsaturated fatty acids and tea polyphenols, as potential modifiers of the angiotensin II–breast cancer association when our cohort has accrued enough incident breast cancer cases to allow for a meaningful analysis of such potential interactive effects.

The current study has several other strengths. Singapore is a small city-state with good access to specialized medical care. The nation-wide cancer registry has been in place since 1968 and has been shown to be comprehensive in its recording of cancer cases (34). Thus, breast cancer case ascertainment can be assumed to be complete. The study allows for the adjustment of known environmental risk factors for breast cancer, all of them assessed prior to cancer diagnosis and thus can be presumed to be free of recall bias.

The chief limitation of our study is a lack of information on use of AGTR1 antagonists and ACE inhibitors, which are commonly prescribed for patients with hypertension, heart disease or diabetes. When we repeated the analysis after excluding subjects with these medical conditions, the results of the gene–cancer associations remained essentially the same, suggesting that the use of these drugs was not a significant confounder. If use of these drugs were to exert a confounding effect on the observed AGTR1 and ACE genotype–breast cancer associations, our inability to control for such confounding is likely to lead to an underestimation, rather than an overestimation, of the protection associated with the putative low risk genotypes. This is because the influence of angiotensin II on the pathophysiology of hypertension, cardiovascular disease and diabetic nephropathy is such that patients with these medical conditions are likely to carry the high activity genotypes of the AGTR1 or ACE gene polymorphisms. Another limitation of the study is its relatively small sample size of breast cancer cases. However, this long-term cohort study will continue to accrue incident cases of breast cancer and will allow for the confirmation (or refutation) of our current findings.

The human AGTR1 gene is mapped to chromosome 3q21–25 and spans >55 kb with 5 exons. Previous studies on the 5'-flanking region of the AGTR1 gene showed that this region contains many regulating elements, such as SP1 recognition sequences and CAAT boxes (35). Deletion of the 5'-flanking region up to position –114 resulted in a >20-fold increase in reporter activity in a chloramphenicol acetyltransferase gene assay, thus indicating the presence of a negatively regulating element(s) in the upstream region within the 2.5 kb of the 5'-flanking region (36). This latter observation prompted us to investigate the association between genetic variations in this region and breast cancer risk. The three gene polymorphisms that we examined in this paper were previously characterized in haplotype association with other genetic variants. We observed a high degree of linkage among the A-168G, C-535T and T-825A polymorphisms of the AGTR1 gene, consistent with these prior data (22,23,37). Our frequency of 19% for the T allele in the C-535T polymorphism was closer to the 14% described among Japanese (23) than to the 36% described among Europeans (22). The frequency of the A allele for the T-825A polymorphism was 12% in our study population. This was also lower than the allelic frequency of 18% among Europeans (22).

To our knowledge, the three polymorphisms under study have not been examined in any gene expression assays in vitro or phenotypic measurement assays in vivo. There are very limited empirical data based on genotype–disease association studies in humans. Poirier et al. stated that the less common A allele of the T-810A gene polymorphism is associated with a lower risk of myocardial infarction. Our observation of a protective effect of the A allele is consistent with the results of Poirier et al. (22), both indirectly suggesting that presence of the A allele is associated with a lower receptor activity/level. A study of modest sample size has examined the C-535T polymorphism in relation to risk of hypertension and noted an association between hypertension and the T allele (23). Another study, which was also of modest sample size, investigated the relationship between age and aortic arterial stiffness in hypertensive subjects >55 years of age and described a steeper regression slope in subjects with one or two copies of the G allele compared with those with the AA genotype of the A-168G polymorphism (21). However, the direction of change in receptor expression/activity between the alleles of these two latter gene polymorphisms were the opposite of those suggested by the empirical observations of our current study. Further work in relevant cell culture models is needed in order to clarify the functionality and the direction and magnitude of the possible functional differences between the different alleles of the studied polymorphisms.

In summary, the present study provides further epidemiological evidence for an etiological role of angiotensin II in breast cancer development. This angiotensin II–breast cancer model has potential implications from the public health perspective. Since the effect of angiotensin II may be modulated in the body using drugs that inhibit either its production or its effects on the receptors, our observations suggest that the use of these drugs to control hypertension and related disease may have practical implications in the prevention and treatment of breast cancer.


    Acknowledgments
 
We thank Ms Siew-Hong Low of the National University of Singapore for supervising the field work of the Singapore Chinese Health Study, and Ms Kazuko Arakawa of the University of Southern California for the development and management of the cohort study database. This work was supported by grants R01 CA55069, R35 CA53890, and R01 CA80205 from the National Cancer Institute, Bethesda, Maryland.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received August 28, 2004; revised September 30, 2004; accepted October 1, 2004.





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