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Genetic Polymorphism of Cytochrome P450–1B1 and Risk of Breast Cancer¹

School of Public Health and South Carolina Cancer Center, University of South Carolina [W. Z., D-W. X., Q. D., X-O. S.], University of South Carolina School of Medicine and South Carolina Cancer Center [W-Q. W., X-O. S.], Columbia, South Carolina 29203, and Shanghai Cancer Institute, Shanghai 200032, China [F. J., J-R. C., Q. D., Y-T. G.]

	Abstract

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Cytochrome P450–1B1 (CYP1B1) is a major enzyme catalyzing the formation of genotoxic 4-hydroxyestradiol. This enzyme is also involved in the activation of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, mammary carcinogens in experimental animals. CYP1B1 is genetically polymorphic, and the variations in the CYP1B1 gene may be related to the risk of breast cancer. We evaluated this hypothesis among 186 breast cancer cases and 200 age-matched controls as part of a large population-based case-control study conducted in urban Shanghai during 1996 to 1998. Genomic DNA from cases and controls was analyzed for genetic polymorphism in codon 432 (ValLeu) of the CYP1B1 gene using a PCR-RFLP-based assay. The frequency of the Leu allele was 53% in cases and 46% in controls (P = 0.06). Compared with those with the Val/Val genotype, women with the Leu/Leu genotype had a 2.3-fold [95% confidence interval (CI), 1.2–4.5] elevated risk of breast cancer after adjusting for potential confounding variables. This positive association was more pronounced among postmenopausal women (Odds ratio, 3.1; 95% CI, 1.0–9.1) than premenopausal women (OR, 1.9; 95% CI, 0.8–4.3). Elevated risks of breast cancer associated with homozygosity for the Leu allele were observed in virtually all subgroups of women defined by major risk factors for breast cancer. The results from this study were consistent with recent findings from in vitro and animal experiments implicating a potentially important role of CYP1B1 in the etiology of human breast cancer.

	Introduction

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CYP1B1³ has been identified recently as one of the most important enzymes catalyzing the formation of 4-hydroxyestradiol (1 , 2) , a catechol estrogen metabolite that retains significant estrogenic activity (1 , 2) . This estrogen metabolite can also undergo metabolic redox cycling to generate potentially mutagenic free radicals that may damage DNA and other cell structures (2 , 3) . In the hamster kidney tumor model, 4-hydroxyestradiol has been shown to be carcinogenic, whereas 2-hydroxyestrogens, another major group of catechol estrogen metabolites, do not induce any tumor (2 , 3) . Although estrogen 4-hydroxylation is a relatively minor pathway in the liver for the formation of catechol estrogens, significant estrogen 4-hydroxylase activity has been observed in several extrahepatic estrogen target tissues (2, 3, 4, 5) , including human mammary epithelial cells (2, 3, 4, 5) . The activity of CYP1B1 was found to be higher in breast cancer than its adjacent normal tissue (6) , suggesting that this enzyme may be involved in the pathogenesis of breast cancer.

Catechol estrogens, including 4-hydroxyestradiol, are metabolically inactivated by catechol-O-methyltransferase (COMT; Ref. 3 ). Recently, a variant COMT allele that is associated with reduced enzyme activity has been linked to elevated risk of breast cancer in several epidemiological studies (7, 8, 9) , including our study among Chinese women in Shanghai (9) . This suggests further that 4-hydroxyestradiol, and thus its metabolic enzyme CYP1B1, may be involved in the etiology of breast cancer.

In addition to catalyzing the formation of 4-hydroxyestradiol, CYP1B1 has also been shown to be involved in the metabolic activation of certain environmental procarcinogens, including polycyclic aromatic hydrocarbons and heterocyclic aromatic amines (10 , 11) , potent mammary carcinogens in experimental animals (12, 13, 14) . In some experiments, CYP1B1 has been shown to be even more active than CYP1A1 in the activation of several polycyclic aromatic hydrocarbons to genotoxic intermediates (11) . The expression of the CYP1B1 gene in human breast epithelial cells suggests that this enzyme may play an important role in the in situ activation of both environmental carcinogens and endogenous estrogens.

The CYP1B1 gene is located in chromosome 2p21-p22 and contains three exons (15, 16, 17) . The entire coding sequence of the genes, however, is contained in exons 2 and 3 (15, 16, 17) , and exon 3 encodes the heme-binding region of the enzyme (18) . A G-to-C transversion at exon 3 was reported to result in a valine (GTG) to leucine (CTG) substitution in codon 432 (17) . This change creates an Eco57I restriction site, making detection of this polymorphism in large epidemiological studies cost efficient. Prompted by the discovery of this easily identifiable polymorphism and findings from recent laboratory studies showing an important role of CYP1B1 in the metabolic activation of estrogens and environmental mammary carcinogens, we evaluated the relation between CYP1B1 genotype and breast cancer risk in a subset of women who participated in the Shanghai Breast Cancer Study.

	Materials and Methods

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The Shanghai Breast Cancer Study is a population-based case-control study conducted among Chinese women in Shanghai, the largest city on the east coast of China with a population of over six million residents (19) . This study was designed to recruit all eligible breast cancer cases who were 25 to 64 years of age and newly diagnosed with breast cancer during the period of August 1996 to March 1998, as well as a representative random sample of controls from the general population. All cases and controls were permanent residents of urban Shanghai who had no prior history of cancer and were alive at the time of interview. Through a rapid case-ascertainment system, supplemented by the population-based Shanghai Tumor Registry, 1602 eligible breast cancer cases 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 prior to interview (17 cases, 1.1%), and inability to locate (17 cases, 1.1%). Cancer diagnoses for all patients were confirmed by two senior study pathologists through the review of tumor slides.

Controls were randomly selected from the female general population and frequency-matched to cases by age (5-year intervals). The number of controls in each age-specific stratum was determined in advance according to the age distribution of the incident breast cases reported to the Shanghai Tumor Registry during 1990–1993. The Shanghai Resident Registry, which keeps registry cards for all adult residents in urban Shanghai, was used to randomly select controls. For each age-predetermined control, a registry card identifying a potential control of the same 5-year age group was randomly selected. Only the women who lived at the address during the study period were considered to be eligible for the study. In-person interviews were completed for 1556 (90.3%) of the 1724 eligible controls identified. Reasons for nonparticipation included refusal (166 controls, 9.6%) and death or a prior cancer diagnosis (2 controls, 0.1%).

A structured questionnaire was used to elicit detailed information on demographic factors, menstrual and reproductive history, hormone use, dietary habits, prior disease history, physical activity, tobacco and alcohol use, weight, and family history of cancer. All participants were also measured for their current weight, circumferences of the waist and hip, and sitting and standing heights. Among those who completed the in-person interviews, blood samples, 10 ml from each woman, were collected using EDTA or heparin Vacutainer tubes from 1193 (82%) cases and 1310 (84%) controls. These samples were processed on the same day at the Shanghai Cancer Institute, and buffy coats (WBCs) for each participant were aliquoted into two 2-ml vials and stored -70°C.

Only a subset of subjects (200 cases and 200 controls) was included in the current study to better use the limited funds available for this substudy. With this sample size, we had 85% statistical power to detect a 2-fold or higher risk of breast cancer for factors with a 20% frequency (type 1 error, 0.05, two-sided). The subjects included in this study were primarily from those who were recruited in the early phase of the Shanghai Breast Cancer Study, because the genotyping work was initiated prior to the completion of the main study. Fourteen patients with a diagnosis of benign breast disease were accidentally included in the initial case group and were subsequently excluded from the analysis. Genomic DNA for cases and controls was extracted from buffy coat fractions using the method described previously (20) . Briefly, frozen WBCs were thawed at the room temperature and then digested overnight at 55°C in 500 µl lysis buffer [50 mM Tris-HCl (pH 8.5), 1 mM EDTA, 0.2% SDS, and 200 µg/ml proteinase K]. The digestion was precipitated directly with isopropanol, and the pellets were washed with 70% ethanol. The genomic DNA pellets (50–100 µg) were dissolved in 300–800 µl of Tris-EDTA buffer. Genomic DNA (10–100 ng) was used for each PCR reaction.

CYP1B1 genotypes were determined using a PCR-RFLP-based assay. According to the published sequence of the human CYP1B1 gene, we designed two primers (forward, 5'-TCACTTGCTTTTCTCTCTCC; reverse, 5'-AATTTCAG-CTTGCCTCTTG) to amplify a 650-bp fragment of exon 3. The PCR reactions were performed on Perkin-Elmer GeneAmp System 9700 according to the manufacturer’s protocol. Specifically, these reactions were carried out in 50 µl of volume of 20 mM Tris-HCl (pH 8.4), 50 mM KCl, 1.0 mM MgCl₂, 0.2 mM deoxynucleotide triphosphate, 1 unit of Taq polymerase, and 0.4 µM of each oligonucleotide primer. The reactions were heated to 94°C for 1 min, followed by 35 cycles of 94°C for 30 s, 60°C for 30 s, and 72°C for 40 s. At the end, the reactions were extended for 7 min at 72°C. Each PCR product was subjected to Eco57I digestion prior to electrophoresis. The DNA fragments were then separated using 3% 2:1 Nusiev/SeaKern agarose gel. The allele types were determined as follows: two fragments of 310- and 340-bp for the Leu allele (CTG), and a single 650-bp fragment for the Val allele (GTG). Representative genotypes are shown in Fig. 1 . To monitor the quality of laboratory work, a second tube of 20 study samples was included in the genetic assays. Laboratory staff were blinded to the identification of the quality control samples. The genotypes for 20 women that were determined from the first and second tubes were in complete agreement.

View larger version (56K): [in this window] [in a new window]   Fig. 1. Gel electrophoresis after RFLP analysis of the 650-bp CYP1B1 PCR product. Representative genotypes are shown in Lane 1 (homozygous for the Leu allele), Lane 2 (heterozygous for the Leu allele), and Lane 3 (homozygous for the Val allele).

	Results

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Table 1 compares the distributions of cases and controls by selected demographic characteristics and major risk factors for breast cancer. Breast cancer cases and controls were comparable in age and education level. With the exception of family history of breast cancer, positive associations were observed for all major risk factors for breast cancer, although the ORs were statistically significant only for a prior history of breast fibroadenoma, no leisure physical activity, and late age at first live birth. These three factors were included in these multivariate analyses as potential confounders. The lack of statistically significant associations with other breast cancer risk factors may be attributable to the small sample size of this substudy.

	Discussion

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The functional significance of the Val⁴³²Leu polymorphism has not been studied adequately. Because exon 3 encodes for the heme-binding region of the CYP1B1 enzyme, nucleotide changes in this exon may be significant to the function of this enzyme. Bailey et al. (21) reported that Caucasian patients with the Val/Val genotype had a significantly higher percentage of breast cancer that were positive for ERs or PRs, suggesting that this polymorphism may be functionally important for the expression of these steroid receptors in breast cancer (21) . Because the prognosis for ER/PR-positive cancer is better than ER/PR-negative cancer, case-control studies including prevalent cases may be subjective to survival bias. In other words, the Val/Val genotype may be overrepresented in prevalent cases, which may attenuate the positive association, if any, with the Leu/Leu genotype. In our study, all breast cancer cases were newly diagnosed, and only 1.1% of eligible cases were missed because of death prior to interviews. Therefore, the potential for survival bias should be minimal in this study. We found that the Leu/Leu genotype was associated with an elevated risk of breast cancer. Furthermore, the positive association between the Leu/Leu genotype and breast cancer was more pronounced among postmenopausal women, among whom more breast cancers are reported to be positive for ERs and/or PRs than those diagnosed among premenopausal women. We were unable at present to evaluate directly the association of CYP1B1 genotypes with subtypes of breast cancer defined by steroid receptors, because no such data were collected.

In addition to estrogen 4-hydroxylation, estrogen hydroxylations also occur at C2, C6, C15, and C16 positions. Among them, estrogen C2 and C16 hydroxylation are of particularly biological and quantitative importance (2) . Similar to 4-hydroxyestrogen, 16-hydroxyestrone has been shown to be genotoxic, reacting with DNA to form adducts (2) . On the other hand, 2-hydroxyestrogen has no estrogenic effect, and in fact, 2-methoxyestrogen may act as an antiestrogen in estrogen-sensitive tissues (2 , 3) . CYP1B1 primarily catalyzes estrogen 4-hydroxylation (2) . We found that the positive association of the CYP1B1-Leu allele with breast cancer was stronger among postmenopausal than premenopausal women. Because the estrogen level is higher among premenopausal than postmenopausal women, our findings suggest that this polymorphism might be more closely related to the activation of environmental mammary carcinogens than estrogen 4-hydroxylation. Very recent data from in vitro experiments suggested that the isozyme encoded by the Leu allele might have an elevated activity in the activation of mammary carcinogens but a reduced activity in estrogen 4-hydroxylation (22) .

The methodological limitations of this study were few. The participation rate of this study was high, minimizing potential selection bias that is common to many case-control studies. Chinese women living in Shanghai are relatively homogeneous in ethnic backgrounds, because >98% of them are classified into a single ethnic group (Han Chinese). We have also compared the place of birth between cases and controls and found that these two groups of women were very similar. Therefore, the potential confounding effect by ethnicity in association studies of genetic biomarkers, may not be a major concern in our study. The sample size in this study was not large, which may have resulted in a relatively unstable estimate of risk, particularly in stratified analyses. Nevertheless, the results from this study are consistent with the observations from laboratory investigation, implicating a potential important role of the CYP1B1 enzyme in the etiology of breast cancer. Our findings are thus biologically plausible and merit further investigation with a larger sample size or in other ethnic populations.

	Acknowledgments

 
We are grateful to Dr. Kim Creek for providing laboratory space and logistical support for this project. We also thank Dr. Zhong-Ling Deng for performing assays for part of the study samples, Dr. Bao-Tin Zhu for helpful comments and suggestions on the manuscript, and Kathy Coats for assistance in manuscript preparation.

	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 in part by USPHS Grant R01-CA64277 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at School of Public Health, University of South Carolina, 15 Richland Medical Park, Suite 301, Columbia SC 29203. Phone: (803) 434-1612; Fax: (803) 434-1626.

³ The abbreviations used are: CYP1B1, cytochrome P450–1B1; OR, odds ratio; CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor.

Received 3/31/99; revised 11/ 2/99; accepted 11/30/99.

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