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[Cancer Research 63, 5727-5730, September 15, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Association of Breast Cancer Risk with a GT Dinucleotide Repeat Polymorphism Upstream of the Estrogen Receptor-{alpha} Gene1

Qiuyin Cai2, Yu-Tang Gao, Wanqing Wen, Xiao-Ou Shu, Fan Jin, Jeffrey R. Smith and Wei Zheng

Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232 [Q. C., W. W., X-O. S., J. R. S., W. Z.], Medical Research Service, VA Tennessee Healthcare System, Nashville, TN 37212 [J. R. S.] and Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China 200032 [Y-T. G., F. J.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Recent studies suggest that genetic polymorphisms of the estrogen receptor-{alpha} (ER-{alpha}) gene may be associated with breast cancer risk. To evaluate the role of this gene in the risk of breast cancer, we genotyped a newly identified GT dinucleotide repeat [(GT)n] polymorphism located in the promoter region (6.6 kb upstream of the transcription start site) in 947 breast cancer cases and 993 age frequency-matched community controls from a population-based case-control study conducted among Chinese in urban Shanghai. Sixteen alleles were identified, the most common one having 16 GT repeats [(GT)16]. Compared with subjects homozygous for this allele, subjects carrying the (GT)17 or (GT)18 allele had a decreased risk of breast cancer. The odds ratios (ORs) were 0.81 [95% confidence interval (CI), 0.62–1.06] and 0.58 (95% CI, 0.36–0.94), respectively, for one and two copies of the (GT)17 or (GT)18 allele. The inverse association with carrying either of these alleles was stronger among women with >30 years of menstrual cycles (OR 0.66; 95% CI 0.51–0.85) than those with a shorter duration of menstrual cycles (OR 0.97; 95% CI 0.73–1.27), and the test for an interaction was statistically significant (P = 0.04). Among breast cancer patients, the presence of either the (GT)17 or (GT)18 allele was associated with a reduced expression of progesterone receptor. Results of this study indicate that the GT dinucleotide repeat polymorphism in ER-{alpha} gene promoter region may be a new biomarker for genetic susceptibility to breast cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Estrogen influences the growth, differentiation, and function of breast and several other target tissues (1) . The biological effect of estrogens, such as stimulating growth and differentiation of normal mammary tissue, is mediated primarily through high-affinity binding to ERs3 (2) . Among the steroid receptors, ER-{alpha} and the ER-regulated PR are of special interest because their protein levels are elevated in premalignant and malignant breast cells (3) . The association of genetic polymorphisms in the ER-{alpha} gene and the risk of diseases, including breast cancer, have been the subject of increasing interest. Although the human ER-{alpha} gene cDNA was cloned in 1986 (4) , and its genomic organization was described in 1988 (5) , the structure of this gene is poorly understood. The ER-{alpha} gene is a large complex genetic unit that spans approximately 300 kb of chromosome 6 (6) . Recently, a GT dinucleotide repeat [(GT)n] polymorphism was noted in the promoter region of the ER-{alpha} gene. The GT repeat is located 6627 bp upstream of the transcription start site of exon 1 and 144 kb downstream of the first untranslated exon E2 (7) . The association of this repeat polymorphism with disease has not been investigated. In this article, we reported results from a large population-based case-control study that examined the association of ER-{alpha} gene (GT)n polymorphism with the risk of breast cancer.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Study Subjects.
Cases and controls in this study were participants of the Shanghai Breast Cancer Study, a population-based case-control study. Detailed study methods have been published elsewhere (8 , 9) . Briefly, this study included 1459 women between the ages of 25 and 64 years and diagnosed with breast cancer between August 1996 and March 1998 and 1556 age frequency-matched control women. The study protocol was approved by committees of relevant institutions for the use of human subjects in research. A total of 1602 eligible cases with breast cancer were identified during the study period, and in-person interviews were completed for 1459 (91%) of them. The major reasons for nonparticipation were refusal (109 cases, 6.8%), death before the interview (17 cases, 1.1%), and the inability to locate (17 cases, 1.1%). Cancer diagnoses for all patients were confirmed by two senior study pathologists. The information on ER and PR status was abstracted from the medical charts of 956 of the 1459 breast cancer cases.

Controls were selected using the Shanghai Resident Registry, a population registry containing demographic information for all residents of urban Shanghai, and were frequency matched on age (5-year intervals) to the expected age distribution of the cases in a 1:1 ratio. The inclusion criteria for controls were identical with those of the cases with the exception of a breast cancer diagnosis. Of the 1724 eligible women, 1556 (90.3%) completed in-person interviews. The remaining women were not included in the study because of either refusal (166, 9.6%) or death before interview (2, 0.1%).

A structured questionnaire was used to elicit detailed information on demographic factors, menstrual and reproductive histories, hormone use, dietary habits, prior disease history, physical activity, tobacco and alcohol use, weight, and family history of cancer. All participants were measured for their current weight, circumference of the waist and hip, and height while sitting and standing. Blood samples were obtained from 1193 (82%) cases and 1310 (84%) controls who completed the in-person interviews. These samples were processed on the same day, typically within 6 h of the sample collections, and stored at -70°C until relevant bioassays.

Genotyping Method.
Genomic DNA was extracted from buffy coat fractions. Genotyping for the (GT)n polymorphism was performed by detection of fluorescent amplimers on an ABI PRISM 3700 automated DNA analyzer. Primers were designed using a tailing strategy to promote full nontemplated nucleotide addition by AmpliTaq Gold DNA polymerase (Applied Biosystems, Foster City, CA), providing unambiguous detection of alleles separated by 1 bp (10) . The primers were: forward 5'-gtgtCTGCTCAAATCTCCTCTG and reverse 5'-GTTAAGAAGGGCCTTTAC-3'. The forward primer was labeled with 6-carboxyfluorescein. Each 2.2 µl of PCR mixture included 0.1 unit of AmpliTaq Gold DNA polymerase, 1x Buffer II, 2.5 mM MgCl2, 0.25 mM dNTPs, 335 nM concentrations of each primer, and 1 ng of DNA. Thermal cycling conditions were as follows: 95°C for 10 min followed by 10 cycles of 94°C for 15 s, 55°C for 15 s, and 72°C for 30 s; 20 cycles of 89°C for 15 s, 55°C for 15 s, and 72°C for 30 s with a final extension step of 72°C for 10 min.

Allele fragment size estimation was accomplished using the internal size standard Genescan 400HD ROX and the Local Southern algorithm of GENESCAN software. Editing of alleles was performed in GENOTYPER. Allele binning and adjustment of run mobility according to control alleles of CEPH 1347-02 were accomplished by custom software. The number of repeats within a GT repeat allele was confirmed by direct sequencing using BigDye Terminator Chemistry on an ABI PRISM 3700 automated DNA analyzer. Each 96-well plate of genomic DNA contained multiple controls, including a water blank, two samples of CEPH 1347-02, two public study control duplicates, and two blinded study control duplicates. Duplicates were distributed across separate 96-well plates. The ABI3700 DNA analyzer has a single laser and an approximate 3-fold attenuation of signal across the capillary array, translating as weaker signal in wells to the left in a 96-well plate. Consequently, the genotype assay failure rate could be higher among those samples. To preclude this as a potential source of bias, samples were arrayed such that equal numbers of cases and controls were present in any given plate column. Genotyping data were obtained from 947 (79.4%) cases and 993 (75.8%) controls who gave blood samples. The major reasons for incomplete genotyping were insufficient DNA and unsuccessful PCR amplification.

Statistic Analysis.
{chi}2 statistics were used to evaluate case-control difference in the distribution of genotypes. To accommodate the age frequency-matched study design, we used logistic regression models conditioned on age to estimate ORs and 95% CIs to measure the strength of the association between ER-{alpha} gene (GT)n polymorphisms and breast cancer risk (11 , 12) . Analyses stratified by menopausal status were conducted to check the homogeneity of the association. Further analyses stratifying years of menstrual cycles and BMI were conducted to evaluate the potential modifying effects of these variables on the association between ER-{alpha} genotypes and breast cancer risk. All statistical tests were two-sided.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
The distributions of selected demographic characteristics and major risk factors for breast cancer in the Shanghai Breast Cancer Study have been previously reported (8 , 9) . Breast cancer cases and controls were comparable in age and education level. Elevated risks of breast cancer were observed for all known major breast cancer risk factors (13) , including a prior history of breast fibroadenoma, physical inactivity, higher waist:hip ratio, higher BMI, early onset of menarche, late onset of menopause, and late age at first live birth.

A total of 16 GT repeat alleles were observed in our study population, ranging from 11 repeats [denoted as (GT)11] to 27 repeats [denoted as (GT)27] (Table 1)Citation . Among them, alleles (GT)15, (GT)16, (GT)17, (GT)18, and (GT)23 were relatively common, each with a frequency of >5%. The (GT)16 allele present in 41.5% of cases and 37.6% of controls was the most common allele in the Chinese population. Overall, the case-control difference in allele distribution was not statistically significant (P = 0.207). When comparing the frequency of each allele with that of all other alleles combined, case-control differences were significant or of borderline significance for three [(GT)16, (GT)17, and (GT)18] of the five common alleles with a frequency of >5% in the control group.


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  		Table 1 Allele frequency of (GT)n polymorphism in the ER-{alpha} gene in breast cancer cases and controls: the Shanghai Breast Cancer Study

 
Table 2Citation shows the association of (GT)n polymorphism and breast cancer risk. We selected subjects homozygous for the most common allele [(GT)16/(GT)16] as the reference group in the initial OR estimations. Genotypes containing the (GT)17 or (GT)18 allele were, in general, associated with a decreased breast cancer risk. The lowest age-adjusted OR was observed in subjects carrying two copies of the (GT)17 or (GT)18 allele (OR 0.58; 95% CI 0.36–0.94; Table 2Citation ). Additional adjustment of physical activity, BMI, waist:hip ratio, age at menarche, live birth, age at first birth, and breast cancer family history had no appreciable effect on age-adjusted ORs (OR with additional adjustment, 0.57; 95% CI 0.35–0.92). Age-adjusted ORs were thus presented in further analyses. We then focused the analyses on the genotypes with the (GT)17 or (GT)18 allele. To increase statistical power, all other groups without the (GT)17 and (GT)18 alleles were combined into one group to serve as the reference group because the ORs of these groups are very close to 1. The presence of the (GT)17 or (GT)18 allele was associated with a significantly decreased breast cancer risk in a dose-response manner with ORs of 0.82 (95% CI 0.68–1.00) and 0.59 (95% CI 0.38–0.92) for one and two copies of the (GT)17 or (GT)18 allele, respectively (P for trend, 0.005). The inverse association of the presence of the (GT)17 or (GT)18 allele with breast cancer risk was more evident among postmenopausal women (OR 0.60; 95% CI 0.43–0.81) than that among premenopausal women (OR 0.94; 95% CI 0.74–1.18; Table 2Citation ). In premenopausal women, a reduced risk of breast cancer was observed among those with two copies of the (GT)17 or (GT)18 allele (OR 0.52; 95% CI 0.30–0.90) but not among those with only one copy of these alleles (OR 1.02; 95% CI 0.80–1.29). The sample size, however, was small in the stratified analyses, particularly for the group with two copies of the (GT)17 or (GT)18 allele.


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  		Table 2 Association between (GT)n polymorphism in the ER-{alpha} gene and breast cancer risk: the Shanghai Breast Cancer Study

 
Further analyses were conducted to evaluate the association of the (GT)n polymorphism and breast cancer risk by duration (years) of menstruation and BMI, factors related to the duration and level of estrogen exposure (Table 3)Citation . The ORs for the presence of the (GT)17 or (GT)18 allele were low in all strata defined by these two factors, particularly among subjects with a longer years of menstrual cycles (and thus longer duration of estrogen exposure). The test for interaction between carrying the (GT)17 or (GT)18 allele and years of menstrual cycles was statistically significant in analyses including all subjects (P = 0.04). The modifying effect of BMI on the association between ER-{alpha} gene (GT)n polymorphism and breast cancer risk was not apparent, although the association appeared strong among women with a higher BMI in the analysis including all subjects.


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  		Table 3 Associations of breast cancer risk with (GT)n polymorphism in the ER-{alpha} gene, stratified by years of menstrual cycle and BMI: the Shanghai Breast Cancer Study

 
We further evaluated the association of (GT)n polymorphism with tumor ER/PR status among breast cancer patients. The presence of the (GT)17 or (GT)18 allele was associated with a reduced expression of PR. A total of 633 breast cancer patients had known PR status in this study. The proportion of breast cancer patients carrying either one of the (GT)17 or (GT)18 allele in the PR-positive group was 37.7% (155 of 411), and that in the PR-negative group was 26.6% (59 of 222; P = 0.0047). No apparent association was found for (GT)n polymorphism and ER status in tumors.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Recent evidence suggests that the human ER-{alpha} gene is transcribed from at least seven promoters into multiple transcripts that all vary in their 5'-untranslated regions (6) . Nine upstream exons have been identified to date, and all upstream exons are spliced to the acceptor splice site at position +163 in coding exon 1 (6) . It is likely that several promoters and exons exist that are perhaps used in only a selected range of cell types or tissues. The GT dinucleotide repeat is located 6627 bp upstream of the transcription start site of exon 1 and 144 kb downstream of the first untranslated exon E2. We have found in this study that the ER-{alpha} gene GT dinucleotide repeat is highly polymorphic and is associated with breast cancer risk in Chinese women. Women carrying the (GT)17 or (GT)18 allele had a substantially decreased risk of breast cancer. However, it remains unclear how breast cancer risk is affected by a variation in the number of STR of this ER-{alpha} gene polymorphism. An increasing number of intronic STRs have been found to interfere with transcription processes by their effect on secondary DNA structure or other unknown mechanisms (7) . Nontranscribed STRs have been shown to nucleate nucleosome formation, and some may act as protein-binding sites (7) . The STR polymorphism may have an impact on the expression of other genes by influencing the transcription and/or stability of mRNA of those genes. In addition, the STR polymorphism may be in LD with exon alterations that may affect ER protein function. Moreover, the STR polymorphism in the ER-{alpha} gene may be linked with alterations of other unidentified genes adjacent to the ER-{alpha} gene, which modulates breast cancer risk (14) .

Several other DNA sequence variations in the ER-{alpha} gene have been reported. We have shown previously that a PvuII polymorphism in the ER-{alpha} gene intron 1 was associated with breast cancer risk (9) . Another dinucleotide repeat, the TA repeat, located 1174 bp upstream of transcription start site of exon 1, was identified earlier (15) . There is no study reporting an association of this polymorphism with breast cancer risk. It has been suggested that the TA repeat polymorphism is in LD with PvuII and XbaI polymorphisms in intron 1 (14 , 16) . Pairwise LD between the GT repeat polymorphism and PvuII/XbaI polymorphisms was not significant in our study (data not shown). Because of some technical difficulties, we were unable to genotype the TA dinucleotide repeat polymorphism in our study. Under our assay, the TA STR had a high potential for assay error because of preferential amplification of the small allele, and a 1-bp stutter ladder resulting from an adjacent monomer repeat. Several polymorphisms in the coding region have been identified (e.g., codons 10 and 325). The associations of these polymorphisms with breast cancer risk have been inconsistent from previous studies (2 , 17 , 18) .

A significant interaction with years of menstrual cycles and (GT)n polymorphism was observed in this study. This finding supports the hypothesis that longer estrogen exposure is associated with breast cancer risk. After menopause, a major portion of estrogens is synthesized in the adipose tissue by aromatase, which converts androgens to estrogens. Women with a high BMI, on the average, have high blood estrogen levels (19) . We did not find an apparent modifying effect of BMI on the association between (GT)n polymorphism and breast cancer risk. Endogenous estrogen levels, however, were lower in Chinese women (20) , and BMI was weakly correlated with blood estrogen level in our study. It is possible that in a population with a low estrogen level, the duration of estrogen exposure, as measured by years of menstrual cycles, may be more important than the level of estrogen exposure in the risk of breast cancer.

Although the response rate for the in-person interview was high (>90%) in the study, only ~83% of study participants provided a blood sample to the study, and ~77% of DNA samples were successfully genotyped for the (GT)n polymorphism. We analyzed questionnaire data separately for subjects with genotyping data and those included in the whole study and found that the two groups of subjects were comparable in major known risk factors and demographic characteristics, indicating that the chance of selection bias in this study is likely to be small.

The current study has many strengths: (a) the large sample size, high participation rate, and population-based study design reduced potential selection bias; (b) the extensive information on lifestyle factors allowed a comprehensive evaluation of their interaction or confounding effects on the association of genetic polymorphisms and breast cancer risk. The risk estimates derived from age-adjusted and multivariable adjusted analyses were similar, indicating that confounding effect is unlikely to be a concern in this study; (c) Chinese women living in Shanghai are relatively homogeneous in ethnic backgrounds; >98% of them are classified into a single ethnic group (Han Chinese). Therefore, the potential confounding effect by ethnicity is not a major concern in our study.

In summary, in this population-based case-control study, GT dinucleotide repeat polymorphism in ER-{alpha} gene promoter region was found to be associated with breast cancer risk in Chinese women. This polymorphism may be a new biomarker for genetic susceptibility to breast cancer.


   FOOTNOTES
 
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.

1 Supported by USPHS Grants RO1CA64277 and RO1CA90899 (to W. Z.) and Vanderbilt-Ingram Cancer Center Support Grant P30CA068485 from the National Cancer Institute. Back

2 To whom requests for reprints should be addressed, at Center for Health Services Research, 636 PRB, 2220 Pierce Avenue, Nashville, TN 37232. Phone: (615) 936-1351; Fax: (615) 936-1790; E-mail: qiuyin.cai{at}vanderbilt.edu Back

3 The abbreviations used are: ER, estrogen receptor; PR, progesterone receptor; OR, odds ratio; CI, confidence interval; BMI, body mass index; STR, short tandem repeat; LD, linkage disequilibrium. Back

Received 6/10/03. Revised 7/21/03. Accepted 7/23/03.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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