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Cytochrome P450 1B1 Val432Leu polymorphism and breast cancer risk in Nigerian women: a case control study

Cytochrome P450 1B1 Val432Leu polymorphism and breast cancer risk in Nigerian women: a case... Background: Cytochrome P450 1B1 (CYP1B1) is active in the metabolism of estrogens to reactive catechols and of different procarcinogens. Several studies have investigated the relationship between genetic polymorphisms of CYP1B1 and breast cancer risk with inconsistent results. A G → C transversion polymorphism in the heme-binding region in codon 432 of the gene results in amino acid change (Val → Leu); the Leu allele display increased catalytic efficiency for 4- hydroxylation of estradiol in some experimental systems. Methods: In this study, we utilized a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay to assess the relationship between this polymorphism and breast cancer risk in a case control study including 250 women with breast cancer and 250 controls from four University Teaching Hospitals in Southern Nigeria. Results: Heterozygosity for the CYP1B1 M1 genotype (CYP1B1 M1 [Val/Leu]) was associated with a significant 59% increased risk of breast cancer (OR = 1.59, 95% CI 1.01–2.58) while homozygosity for the genotype (CYP1B1 M1 [Leu/Leu]) conferred a non-significant 51% increased risk of breast cancer. These risk profiles were modified in subgroup analysis. In premenopausal women, harboring at least one CYP1B1 (Leu) allele conferred a significant two-fold increased risk of breast Page 1 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 cancer (OR = 2.04, 95% CI 1.10–3.78). No significant association was observed in postmenopausal women (OR = 1.08, 95% CI 0.57–2.04). Conclusion: Our results suggest that the codon 432 polymorphism of the CYP1B1 gene is associated with increased risk of breast cancer and is particularly involved in breast cancer risk in premenopausal women of African descent. data on the role of polymorphisms in this gene in breast Background Breast cancer has unique racial/ethnic variations in inci- cancer susceptibility in populations of African descent. dence and burden. While the incidence is rising globally, Only one of the US studies recruited a small sample of the increase is occurring faster in population groups that African-American women; there are no studies on sub- hitherto enjoyed low incidence. Reasons for the racial/ Saharan African populations. Although, several polymor- ethnic variation in breast cancer incidence are unclear; phisms have been described in the CYP1B1 gene, we have however, differences in the distribution of polymor- chosen in this exploratory study to evaluate the role of the phisms in key candidate genes involved in estrogen/xeno- CYP1B1 Val432Leu polymorphism in breast cancer sus- biotic metabolism might contribute to variation in breast ceptibility in Nigerian women since there is experimental cancer susceptibility in different populations. The CYP1B1 evidence suggesting that the variant CYP1B1 432Leu allele gene is located on chromosome 2p21-p22 and contains exceeded the wild-type CYP1B1 432Val allele with respect three exons [1-3]. The entire coding sequence of the gene, to estrogen hydroxylation activities. Given the carcino- however, is contained in exons 2 and 3 [1-3]; exon 3 genic and estrogenic potential of 4-OH-E2, it is plausible encodes the heme-binding region of the enzyme [4]. to speculate that inheritance of the CYP1B1 432Leu allele CYP1B1 might be involved in hormonal carcinogenesis may contribute to increased breast cancer risk associated through its ability to catalyze the metabolism of estradiol with estrogen-mediated carcinogenesis. to 2-hydroxyestradiol and 4-hydroxyestradiol [5]. The former metabolite is mainly produced in the liver whereas Materials and methods significant amount of 4-hydroxyestradiol are formed in Subjects extrahepatic tissues. Whereas 2-hydroxyestradiol has little Study participants were recruited between September or no carcinogenic activity, 4-hydroxyestradiol and estro- 2002 and April 2004 in four University Teaching Hospi- gen have been shown to be potent carcinogens in animal tals in Southern Nigeria including University of Benin models [6] and humans [7,8]. In-situ conjugation of this Teaching Hospital, Benin City; Nnamdi Azikiwe Univer- metabolite by phase II enzymes is relatively low in extra- sity Teaching Hospital, Nnewi; University of Nigeria hepatic tissues, thus leading to its accumulation. The car- Teaching Hospital, Enugu; and University of Port Har- cinogenic activity of 4-hydroxyestradiol could be due to court Teaching Hospital, Port Harcourt. The Institutional its hormonal activity, which in some biological assays has Review Board of University of Pittsburgh and the Ethics been shown to be even higher than the parent hormone. and Research Committees of the Nigerian institutions In addition, 4-hydroxyestradiol can undergo redox cycling approved the study prior to commencement. A total of [7] which results in the formation of free radicals such as 500 study participants comprising 250 women with inci- superoxide and in the generation of reactive semiqui- dent and prevalent breast cancer and 250 age- and institu- none/quinone intermediates that have been shown to tion-matched controls were recruited for the study. damage biological target molecules such as DNA [8]. Women with confirmed breast cancer were recruited dur- ing surgical out-patient clinic visits or in-patient admis- Six polymorphisms of the CYP1B1 gene have been sions while control subjects with non-malignant surgical described in the Caucasian populations, of which four diseases such as road traffic accident and other injuries (n results in amino acid substitutions [3,4]. Two of these = 168), intestinal obstructions (n = 49), appendicitis/pel- amino acid substitutions are located in exon 3, which vic inflammatory disease (26), urolithiasis and urinary encodes the heme-binding domain: codon 432 Val → Leu tract infections (n = 5) and cholelithiasis (n = 2) were and 453 Asn → Ser [4] while two other amino acid substi- recruited from the same hospitals. Exclusion criteria tutions are found in codons 48 Arg → Gly and 119 Ala → include non-confirmation of diagnosis of breast cancer, a Ser in exon 2 [3]. The codon 432 Val → Leu polymor- diagnosis of other malignant diseases, and refusal of phism creates and Eco57I site. Several molecular epidemi- donation of blood samples. ological studies have evaluated the association of polymorphisms in CYP1B1 gene and breast cancer risk in Prior to recruitment, participants signed informed con- various populations, including seven in Caucasian [4,9- sent after detailed explanation of key points of the study 14] and four in Asian populations [15-18]. There is scanty including study objectives, risks and benefits, confidenti- Page 2 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 ality and the rights of participants. Interviewer-adminis- containing genomic DNA and a negative control contain- tered questionnaires were used for data collection; ing everything except DNA were included in the PCR questions were designed to gather demographic history experiment. Five μl of each PCR product, including the including age, sex, religion, occupation, exposure to controls, were verified on a 2% agarose gel to ensure that chemical fertilizers and pesticides, and rearing of domes- the expected 650 bp product was generated. tic animals. In addition, obstetric and gynecological his- tory including age at menarche, age at first full-term Restriction digest for the DNA fragment was carried out pregnancy, parity, breastfeeding, age at menopause (for using Eco57I restriction enzyme. Fifteen μl of the PCR postmenopausal subjects), history of use of hormonal product was digested for 16 h overnight at 37°C with 1 contraceptives and hormone replacement therapy and unit of Eco57I (New England Biolabs). The product of the surgical oophorectomy was obtained. Information about restriction digest was mixed with 10 μl of loading dye and lifestyle habits such as cigarette smoking and alcohol con- verified on a 3% agarose gel (with Ethidium bromide) sumption was also obtained from study participants. electrophoresis in a 1× Tris-Borate-EDTA buffer at 200 V Anthropometric measurements including height, weight, for 60 min. The presence of a G at position 1294 waist and hip circumferences were taken at the end of the (CYP1B1-codon 432) generated a unique 650 bp frag- interview. ment, while the 650 bp fragment was divided into unique 340 bp and 310 bp fragments when position 1294 con- Sample donation and preparation tains a C. The gels were visualized by UV light and the Blood samples were collected at the end of the interview; RFLP gel electrophoresis products were read by two inde- details are reported elsewhere [19,20]; 10 ml of whole pendent persons who were unaware of the identities of blood was collected in one 10 ml K -EDTA vacutainer samples as either cases or controls. tube from each of the study participants and stored in ice packs until it was centrifuged within 10 h of collection RFLP assays employing Eco57I restriction enzyme were and buffy coats collected and stored in 3 ml tubes. All the successful in 228 cases and 226 controls, therefore the samples were stored at -20°C in the various study sites in analysis is restricted to this sample of women. Nigeria and later transferred to the Nigerian coordinating Statistical analysis center at the University of Benin Teaching Hospital in Polar Pack -20 C ice packs for frozen shipments and later Statistical analysis was carried out using the Statistical shipped to University of Pittsburgh in dry ice using Analysis System (SAS) software (Version 8.0). Condi- express services. Samples were stored at -80°C at the Uni- tional logistic regression was used to assess the association versity of Pittsburgh until DNA extraction. between the CYP1B1 genotypes and breast cancer risk in the whole sample. Stratified analyses according to meno- DNA extraction was carried out using QIAamp DNA Mini pausal status were carried out. Relevant risk factors that Kits (for buffy coats) and QIAamp DNA Midi Kits (for were identified as significant predictors of breast cancer blood clots) protocols (QIAGEN Inc. Valencia, CA). The risk were controlled for in the multivariate logistic regres- extracted DNA was stored at 4°C until used for PCR and sion models. RFLP analysis. Results PCR and RFLP analysis Demographic characteristics Genomic DNA from the cases and control subjects were Five hundred participants comprising 250 women with analyzed for the presence of the G to C transversion muta- breast cancer and 250 age- and institution-matched con- tion at codon 432 of the CYP1B1 gene by a PCR-based trols were recruited from four University Teaching Hospi- Restriction Fragment Length Polymorphism (RFLP) assay. tals in Midwestern and Southeastern Nigeria. However, PCR amplification of a 650 bp fragment of the CYP1B1 this report is based on data on 228 cases and 226 control gene, including part of exon 3 that contains the polymor- subjects in whom RFLP polymorphism assays on CYP1B1 phism was carried out using forward primer: TCACTT- gene were successful. Mean age of cases and control sub- GCTTTTCTCTCTCC and reverse primer: jects were similar (46.3 ± 11.72 years and 47.3 ± 12.14 AATTTCAGCTTGCCTCCTG. A 50 μl PCR reaction mixture years respectively). Using univariate logistic regression containing 2 μl of genomic DNA, 5 μl of deoxynucleotide models, the following variables including family history triphosphates, 5 μl each of forward and reverse primers, 5 of breast cancer, education, ever married, age at fullterm μl of 10× buffer, 1.5 μl of MgCl and 0.5 μl of Taq pregnancy (FFTP), parity, duration of breastfeeding, abor- polymerase was placed in a thermalcycler. After denatur- tion, use of hormone contraceptives, waist/hip ratio, and ing for 10 min at 95°C, the DNA was amplified for 35 body mass index (BMI) were found to be significant pre- cycles at 95°C for 60 s, 58°C for 60 s, and 72°C for 60 s, dictors of breast cancer risk. However, only three variables followed by a 7 min extension at 72°C. A positive control including Family history of breast cancer (OR = 11.17, Page 3 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 95% CI 1.37–91.33), age at first fullterm pregnancy frequency of the CYP1B1 (Val/Val), CYP1B1 (Val/Leu) greater than 20 years (OR = 1.32, 95% CI 1.17–3.41) and and CYP1B1 (Leu/Leu) genotypes among cases and con- waist/hip ratio (OR = 1.90, 95% CI 1.18–3.04) were sig- trol subjects, as shown in Table 2. All the three nificant predictors of breast cancer risk in the final multi- homozygous variants were control subjects. ple logistic regression model as shown in Table 1. More details on distribution of anthropometric and reproduc- CYP1B1 genotypes and breast cancer risk All women tive variables and their association with breast cancer are reported elsewhere [21,22]. As shown in Table 2, cases were more likely to harbor the Leu allele than the controls. The heterozygous CYP1B1 Allele and genotype frequencies (Val/Leu) genotype was associated with a significant All women increased risk of breast cancer (Odds ratio [OR] = 1.59, The CYP1B1 (Val) allele was less frequent in cases (0.86) 95% Confidence Interval [CI] 1.01–2.52), compared with compared to control subjects (0.89). The distribution of the homozygous wild type CYP1B1 (Val/Val) genotype. the CYP1B1 genotype is shown in Table 2. The genotype There were very few study subjects with the homozygous frequencies of the CYP1B1 (Val/Val), CYP1B1 (Val/Leu) variant CYP1B1 (Leu/Leu), four among the cases and five and CYP1B1 (Leu/Leu) in the cases were 0.73, 0.25, and among the control subjects; this genotype was not associ- 0.02, respectively while the corresponding frequencies in ated with breast cancer (OR = 0.87, 95% CI 0.23–3.30). the control subjects were 0.81, 0.17, and 0.02, respec- tively. The distribution of CYP1B1 (Val/Leu) alleles in the Adjustment for waist/hip ratio (WHR) slightly attenuated control subjects was in Hardy-Weinberg equilibrium, the risk associated with the CYP1B1 1B1 (Val/Leu) geno- overall and in both premenopausal and postmenopausal type in all women (OR = 1.57, 95% CI 0.99–2.51). The women. risk associated with the CYP1B1 (Leu/Leu) (OR = 0.94, 95% CI 0.24–3.64) and the combined CYP1B1 (Val/Leu) Premenopausal women and CYP1B1 (Leu/Leu) genotypes (OR = 1.51, 95% CI Among 142 premenopausal breast cancer cases and 142 0.96–2.36) remained essentially unchanged. premenopausal control women, the RFLP polymorphism Premenopausal women assays were successful in 125 cases and 129 controls. The CYP1B1 (Val) allele was less frequent among premeno- The heterozygous CYP1B1 (Val/Leu) genotype was associ- pausal cases (0.85) compared to the control subjects ated with a significantly increased risk of premenopausal (0.92). As shown in Table 2, the CYP1B1 (Val/Leu) and breast cancer (OR = 2.00, 95% 1.05–3.81; the risk associ- CYP1B1 (Leu/Leu) genotypes were more common in ated with the homozygous genotype (Leu/Leu) did not cases compared with the control subjects. reach significance (OR = 2.40, 95% CI 0.43–13.38). The risk of premenopausal breast cancer with the hetero- Postmenopausal women zygous CYP1B1 (Val/Leu) and homozygous CYP1B1 Of the 108 postmenopausal breast cancer cases and 108 (Leu/Leu) genotypes combined was 2.04 (95% CI 1.10– postmenopausal control subjects, the PCR-based RFLP 3.78) (Table 2). The risk of premenopausal breast cancer assays were successful in 103 cases and 97 control sub- associated with the CYP1B1 genotypes remained essen- jects. The distribution of the CYP1B1 (Val) and CYP1B1 tially unchanged when WHR was included in the model. (Leu) alleles in postmenopausal breast cancer cases and controls were similar. There were slight differences in the Table 1: Multiple conditional logistic regression comparing cases and controls. Significant demographic predictors of breast cancer risk [Numbers (Percentages (%)], odds ratio (OR), 95% confidence interval (95% CI) Variable Cases Controls OR 95% CI Family history breast Yes 14 (6.00) 1 (0.40) 11.17 1.37, 91.33 Cancer No 214 (94.00) 225 (99.60) 1.00 Age at first fullterm Yes 162 (77.20) 136 (65.07) 1.32 1.17, 3.41 Pregnancy (>20 years) No 48 (22.8) 73 (34.93) 1.00 Waist/hip ratio (>0.90) Yes 147 (64.47) 107 (47.35) 1.90 1.18, 3.04 No 81 (35.53) 119 (52.65) 1.00 Page 4 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 Table 2: Distribution of Cytochrome P4501B1 alleles and genotypes in relation to breast cancer risk Cases Controls OR (95% CI) OR (95% CI)* All women (n = 228) (n = 226) Allele frequencies CYP1B1(Val) 0.86 0.89 CYP1B1(Leu) 0.14 0.11 Genotype frequencies CYP1B1 (Val/Val) 167 (47.85) 182 (52.15) 1.00 CYP1B1 (Val/Leu) 57 (59.38) 39 (40.62) 1.59 (1.01–2.52) 1.57 (0.99–2.51) CYP1B1 (Leu/Leu) 4 (44.44) 5 (55.6) 0.87 (0.23–3.30) 0.94 (0.24–3.64) CYP1B1 (Val/Val) 167 (47.85) 182 (52.15) 1.00 CYP1B1 (Val/Leu) + (Leu/Leu) 61 (58.10) 44 (41.90) 1.51 (0.92–2.35) 1.51 (0.96–2.36) Pre-menopausal women (n = 125) (n = 129) Allele frequencies CYP1B1(Val) 0.85 0.92 CYP1B1(Leu) 0.15 0.08 Genotype frequencies CYP1B1 (Val/Val) 91 (45.50) 109 (54.50) 1.00 CYP1B1 (Val/Leu) 30 (62.50) 18 (37.50) 2.00 (1.05–3.81) 1.97 (1.02–3.81) CYP1B1 (Leu/Leu) 4 (66.67) 2 (33.33) 2.40 (0.43–13.38) 2.64 (0.46–15.23) CYP1B1 (Val/Val) 91 (45.50) 109 (54.50) 1.00 CYP1B1 (Val/Leu) + (Leu/Leu) 34 (62.96) 20 (37.04) 2.04 (1.10–3.78) 2.04 (1.07–3.81) Postmenopausal women (n = 103) (n = 97) Allele frequencies CYP1B1(Val) 0.87 0.86 CYP1B1(Leu) 0.13 0.14 Genotype frequencies CYP1B1 (Val/Val) 76 (51.00) 73 (49.00) 1.00 CYP1B1 (Val/Leu) 27 (56.30) 21 (43.80) 1.24 (0.64–2.38) 1.20 (0.62–2.34) CYP1B1 (Leu/Leu) 0 (0.00) 3 (100.00) ** ** CYP1B1 (Val/Val) 76 (51.00) 73 (49.00) 1.00 CYP1B1 (Val/Leu) + (Leu/Leu) 27 (52.94) 24 (47.06) 1.08 (0.57–2.04) 1.05 (0.55–2.01) * Adjusted for waist/hip ratio (WHR) ** Odds ratios could not be determined due to missing values in some cells Postmenopausal women designed to evaluate the hypothesis that the CYP1B1 There was no association between the CYP1B1 polymor- Val432Leu polymorphisms in the CYP1B1 gene, a key phism and breast cancer in post menopausal women. candidate gene involved in phase I hydroxylation of estro- Harboring at least one CYP1B1 (Leu) allele was not asso- gens (17β-estradiol and estrone) to 4-hydroxy catechols ciated with risk of breast cancer in postmenopausal might contribute to breast cancer risk in Nigerian women. women (OR = 1.08, 95% CI 0.57–2.04). Controlling for WHR did not significantly alter the risk profiles (Table 2). Comparison of our data with reports from other popula- tions indicates wide variation in the distribution of the Discussion CYP1B1 codon 432 Val → Leu polymorphism across dif- Breast cancer is a disease with unique phenotypic mani- ferent populations groups. The frequency of the CYP1B1 festations in different racial/population groups. It has (Val) allele among control subjects in our study (0.89) is been hypothesized that these population-specific charac- closer to the frequency in African-Americans (0.70) [4] teristics of breast cancer may be partly due to differences but much higher than the figures reported in Caucasians in genetic susceptibility to the disease arising from varia- (0.42) [9], Asians in China (0.46) [18], Japan (0.15) [17], tion in the frequency of different polymorphic alleles of and Korea (0.11) [16]. key candidate genes involved in estrogen and xenobiotic metabolism in different populations. Our study was Page 5 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 Our results suggest that harboring one CYP1B1 (Leu) A small hospital-based case-control study involving 59 allele was significantly associated with breast cancer (OR African-American women found no statistically signifi- = 1.59, 95% CI 1.01–2.52). Subgroup analysis based on cant association between the CYP1B1 Val432Leu poly- menopausal status showed that the risk conferred by this morphism and breast cancer risk [4]. Of three studies in polymorphism was essentially restricted to premenopau- mixed U.S. populations [25-27], one [26] reported no sig- sal women in whom the combination of CYP1B1 (Val/ nificant association, while two [25,27] reported an inverse Leu) and CYP1B1 (Leu/Leu) genotypes was associated association between the Val/Val genotype and breast can- with over 2-fold increased risk of breast cancer (OR = cer (OR = 0.4, 95% CI 0.1–1.0 and OR = 0.7, 95% CI 0.6– 2.04, 95% CI 1.10–3.78). This association was not con- 0.9, respectively) and for the Val/Val and Val/Leu geno- firmed in postmenopausal women. The associations were types combined (OR = 0.4, 95% CI 0.1–1.0 and OR = 0.8, not significantly modified by the adjustment of the data 95% CI 0.7–0.9, respectively). Meta-analysis of these stud- for waist/hip ratio (a surrogate measure of etiologically ies in African-American and mixed populations showed relevant obesity) in either premenopausal or postmeno- no overall significant risk associated with the CYP1B1 pausal women, despite the finding of preferential 4- Val432Leu polymorphism in breast cancer susceptibility hydroxylation of estrogens in obese women on high fat in these populations [24]. diet [23]. Meta-analysis of studies on the association between Several other investigators have evaluated the relationship CYP1B1 Val432Leu polymorphism and breast cancer risk between CYP1B1 polymorphisms and breast cancer in dif- failed to demonstrate an overall significant association in ferent populations. There appear to be no significant over- Asian women [24]. Of the four available studies, three all association between the CYP1B1 Val/Leu variant and [15,16,26] found no significant association. Only one breast cancer risk in Caucasian populations in a recent study in the Chinese population [18] reported that, com- meta-analysis [24]. However, a pooled analysis suggests a pared with those with the Val/Val genotype, women with possible association of both the Val/Leu and Val/Val gen- the Leu/Leu genotype had a 2.3-fold (95% CI 1.2–4.5) otypes with breast cancer in Caucasians but no significant elevated risk of breast cancer after adjusting for confound- effect was observed in Asians or African-American subjects ing variables, the positive association between the Leu/ [24]. Among the seven studies in Caucasians, three Leu genotype and breast cancer was more pronounced in reported no association between the CYP1B1 Val432Leu postmenopausal women (OR = 3.1, 95% CI 1.0–9.1) than polymorphism and breast cancer risk [4,10,14], while in premenopausal women (OR = 1.9, 95% CI 0.8–4.3). three reported a risk effect for the valine allele [9,11,13]; one study reported an inverse association between the The differences in breast cancer risk associated with the valine allele and breast cancer [12]. Statistical significance CYP1B1 Val432Leu polymorphism in different popula- for the association between breast cancer and the CYP1B1 tions may be due to several reasons including differences Val/Val polymorphism was reached in two studies in frequency of Val and Leu alleles in different popula- [11,13]. In one of these studies, Listgarten et al. [11] tions, the relatively small sample size of some studies found that harboring the heterozygous Val/Leu genotype [4,11,13,25,26], as well as differences in study designs. was associated with a 2.15-fold increased risk of breast cancer (95% CI 1.31–3.52) while the homozygous The mechanisms through which polymorphisms in mutant (Leu/Leu) conferred a 3.30-fold increased risk CYP1B1 might influence breast cancer risk are not com- (95% CI 1.76–6.19). In the second study of 84 cases and pletely known. CYP1B1 is expressed constitutively in ext- 103 controls among the Turkish population, Kobacas et rahepatic tissues including lung and mammary tissue al. [13] reported an overall association between carriers of [28]. Although other cytochrome P450 enzymes, such as at least one Val allele and breast cancer risk among CYP1A2 and CYP3A4, are involved in hepatic and extrahe- women with body mass index (BMI) > 24 kg/m (OR = patic estrogen hydroxylation, CYP1A1 and CYP1B1 dis- 2.81, 95% CI 1.38–3.74). Although Bailey et al. [4] failed play the highest levels of expression in breast tissue [28]; to demonstrate a significant association between the CYP1B1 exceeds CYP1A1 in its catalytic efficiency as an CYP1B1 Val432Leu polymorphism and breast cancer risk, estradiol (E ) hydroxylase, and differs from CYP1A1 in its they noted that Caucasian patients with the Val/Val geno- main site of catalysis [5,29,30]. CYP1B1 has its primary type had a significantly higher percentage of breast cancer activity at the C-4 position of estradiol (E ), whereas that were positive for estrogen receptors (ERs) or proges- CYP1A1 has its primary activity at the C-2 position. These terone receptors (PRs), suggesting that this polymorphism two metabolites differ greatly in their carcinogenicity. may be functionally important for the expression of these Treatment with 4-OH-E , but not 2-OH-E , induced renal 2 2 steroid receptors. cancer in Syrian hamster [7,31]. Analysis of renal DNA demonstrated that 4-OH-E significantly increased 8- hydroxydeoxyguanosine levels, whereas 2-OH-E did not Page 6 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 cause oxidative DNA damage [32]. Similarly, 4-OH-E logical information. In fact, breast cancer is predomi- induced DNA single-strand breaks whereas 2-OH-E had a nantly a premenopausal disease in Nigerian women [37], negligible effect [33]. Comparison of the corresponding with a disproportionately higher prevalence of hormone catechol estrogen quinones showed that E -3,4-quinone receptor negative breast cancer, estimated at about 76% produced two to three orders of magnitude higher levels [38]. These data, together with the observation of a higher of depurinating adducts than E -2,3-quinone. Signifi- proportion of the CYP1B1 (Val) allele among postmeno- cantly higher 4-OH-E /2-OH-E ratios were observed in pausal women with hormone receptor positive breast can- 2 2 breast tumor tissue than in adjacent normal breast tissue cer [4], and of an association between Nigerian [34]. These findings suggest a causative role of 4-OH cate- premenopausal breast cancer and the CYP1B1 (Leu) allele chol estrogens in carcinogenesis and implicate CYP1B1 as suggest that breast cancer in sub-Saharan African popula- a key player in the process. tions may have a different etiopathogenesis than in Cau- casian or Asian populations. The understanding of To the best of our knowledge, ours is the largest case-con- differences in estrogen and xenobiotic metabolism result- trol study on CYP1B1 Val432Leu polymorphism and ing from polymorphic variants in key candidate genes, breast cancer risk conducted in African populations. and their interaction with environmental exposure has the potential to considerably improve our ability to char- The epidemiologic literature on determinants of breast acterize individual risk of breast cancer and enhance our cancer in sub-Saharan African populations is scanty ability to design individual and population-specific con- despite the evidence that breast cancer is already a public trol and preventive measures. health problem in these developing countries [35,36] and the burden of the disease is likely to increase as women in List of abbreviations used these populations adopt Western diets and sedentary life- CYP1B1: Cytochrome P4501B1 gene; DNA: Deoxyribonu- styles. The use of hospital controls instead of population- cleic acid; PCR: Polymerase chain reaction; SNP: Single based controls might be a source of systematic bias; poor Nucleotide Polymorphism; CYP1A2: Cytochrome research infrastructure including the absence of a popula- P4501A2 gene; CYP3A4: Cytochrome P4503A4 gene; E : tion-based cancer registry and lack of functional commu- 17β-estradiol; 2-OH-E : 2-Hydroxy-Estradiol; 2-OH-E : 4- 2 2 Hydroxy-Estradiol; ER: Estrogen receptor; PR: Progester- nication facilities limited our choice of recruitment for the control subjects. Recruitment of incident and prevalent one receptor; SAS: Statistical Analysis Systems. cases of breast cancer may also be a source of systematic bias as women with rapidly progressive forms of breast Competing interests cancer may have died early, leaving us with a subpopula- The authors declare that they have no competing interests. tion of less aggressive prevalent cases. This is particularly important given the report of an interaction between the Authors' contributions CYP1B1 Val → Leu polymorphism and hormone receptor MNO, CHB, ET, SJG, REF, LHK, participated in conceptu- status noted in Caucasian women [4]. The observed pre- alization, design of the study and preparation of manu- ponderance of hormone receptor positive tumors in indi- script; MNO, ERE, SNCA, JO and EEOU recruited study viduals harboring the Val/Val genotype would result in participants from Nigeria and organized the transfer of selective survival advantage of this genotype. However, biological samples to the University of Pittsburgh; MNO, such an interaction if present in our study population CHB, ET, SJG and JMZ carried out the genetic analysis and would result in underestimation of the breast cancer risk manuscript preparation. associated with the presence of the CYP1B1 (Leu) allele. The non-availability of facilities for hormone receptor Acknowledgements This study was supported by a post-doctoral grant awarded to Michael N. assays during the recruitment of study participants in the Okobia by the U.S. Army Medical and Materiel Command's Breast Cancer Nigerian study sites limited our ability to actually evaluate Research Program (Award Number: DAMD17-02-1-0551). We are grate- the presence of such interaction if any. ful to the staff of the Departments of Surgery of the Nigerian Study Sites including University of Benin Teaching Hospital, Benin City; Nnamdi Conclusion Azikiwe University Teaching Hospital, Nnewi; University of Nigeria Teach- This study has demonstrated a role for the CYP1B1 Val → ing Hospital, Enugu; and the University of Port Harcourt Teaching Hospital, Leu polymorphism in premenopausal breast cancer risk in Port Harcourt, for all their assistance during the recruitment of study par- Nigerian women. This polymorphism might be mediating ticipants. Special thanks to the staff of the Department of Epidemiology, University of Pittsburgh for their invaluable assistance throughout the con- its effect through increased metabolic conversion of estra- duct of this study. diol, the main estrogen in premenopausal women, to 4- hydroxy estradiol and estrogen quinone and semiquinone This article has been published as part of Infectious Agents and Cancer. Vol- intermediates. The results we report in this study need to ume 4 Supplement 1, 2009: Second Annual International African-Caribbean be considered in conjunction with clinical and epidemio- Page 7 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 Cancer Consortium Conference. The full contents of the supplement are of breast cancer. Cancer Epidemiol Biomarkers Prev 2000, 9(2):147-150. available online at http://www.infectagentscancer.com/supplements/4/S1. 19. 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Anyanwu SN: Breast cancer in eastern Nigeria: a ten year review. West Afr J Med 2000, 19(2):120-125. Gotoh O, Kawajiri K: Association of CYP1B1 genetic polymor- phism with incidence to breast and lung cancer. Pharmacoge- 38. Ikpatt OF, Ndoma-Egba R: Oestrogen and progesterone recep- tors in Nigerian breast cancer: relationship to tumour his- netics 2000, 10(1):25-33. 18. Zheng W, Xie DW, Jin F, Cheng JR, Dai Q, Wen WQ, Shu XO, Gao topathology and survival of patients. Cent Afr J Med 2003, 49(11–12):122-126. YT: Genetic polymorphism of cytochrome P450-1B1 and risk Page 8 of 8 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

Cytochrome P450 1B1 Val432Leu polymorphism and breast cancer risk in Nigerian women: a case control study

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Springer Journals
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Copyright © 2009 by Okobia et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Cancer Research; Infectious Diseases; Oncology
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1750-9378
DOI
10.1186/1750-9378-4-S1-S12
pmid
19208203
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Abstract

Background: Cytochrome P450 1B1 (CYP1B1) is active in the metabolism of estrogens to reactive catechols and of different procarcinogens. Several studies have investigated the relationship between genetic polymorphisms of CYP1B1 and breast cancer risk with inconsistent results. A G → C transversion polymorphism in the heme-binding region in codon 432 of the gene results in amino acid change (Val → Leu); the Leu allele display increased catalytic efficiency for 4- hydroxylation of estradiol in some experimental systems. Methods: In this study, we utilized a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay to assess the relationship between this polymorphism and breast cancer risk in a case control study including 250 women with breast cancer and 250 controls from four University Teaching Hospitals in Southern Nigeria. Results: Heterozygosity for the CYP1B1 M1 genotype (CYP1B1 M1 [Val/Leu]) was associated with a significant 59% increased risk of breast cancer (OR = 1.59, 95% CI 1.01–2.58) while homozygosity for the genotype (CYP1B1 M1 [Leu/Leu]) conferred a non-significant 51% increased risk of breast cancer. These risk profiles were modified in subgroup analysis. In premenopausal women, harboring at least one CYP1B1 (Leu) allele conferred a significant two-fold increased risk of breast Page 1 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 cancer (OR = 2.04, 95% CI 1.10–3.78). No significant association was observed in postmenopausal women (OR = 1.08, 95% CI 0.57–2.04). Conclusion: Our results suggest that the codon 432 polymorphism of the CYP1B1 gene is associated with increased risk of breast cancer and is particularly involved in breast cancer risk in premenopausal women of African descent. data on the role of polymorphisms in this gene in breast Background Breast cancer has unique racial/ethnic variations in inci- cancer susceptibility in populations of African descent. dence and burden. While the incidence is rising globally, Only one of the US studies recruited a small sample of the increase is occurring faster in population groups that African-American women; there are no studies on sub- hitherto enjoyed low incidence. Reasons for the racial/ Saharan African populations. Although, several polymor- ethnic variation in breast cancer incidence are unclear; phisms have been described in the CYP1B1 gene, we have however, differences in the distribution of polymor- chosen in this exploratory study to evaluate the role of the phisms in key candidate genes involved in estrogen/xeno- CYP1B1 Val432Leu polymorphism in breast cancer sus- biotic metabolism might contribute to variation in breast ceptibility in Nigerian women since there is experimental cancer susceptibility in different populations. The CYP1B1 evidence suggesting that the variant CYP1B1 432Leu allele gene is located on chromosome 2p21-p22 and contains exceeded the wild-type CYP1B1 432Val allele with respect three exons [1-3]. The entire coding sequence of the gene, to estrogen hydroxylation activities. Given the carcino- however, is contained in exons 2 and 3 [1-3]; exon 3 genic and estrogenic potential of 4-OH-E2, it is plausible encodes the heme-binding region of the enzyme [4]. to speculate that inheritance of the CYP1B1 432Leu allele CYP1B1 might be involved in hormonal carcinogenesis may contribute to increased breast cancer risk associated through its ability to catalyze the metabolism of estradiol with estrogen-mediated carcinogenesis. to 2-hydroxyestradiol and 4-hydroxyestradiol [5]. The former metabolite is mainly produced in the liver whereas Materials and methods significant amount of 4-hydroxyestradiol are formed in Subjects extrahepatic tissues. Whereas 2-hydroxyestradiol has little Study participants were recruited between September or no carcinogenic activity, 4-hydroxyestradiol and estro- 2002 and April 2004 in four University Teaching Hospi- gen have been shown to be potent carcinogens in animal tals in Southern Nigeria including University of Benin models [6] and humans [7,8]. In-situ conjugation of this Teaching Hospital, Benin City; Nnamdi Azikiwe Univer- metabolite by phase II enzymes is relatively low in extra- sity Teaching Hospital, Nnewi; University of Nigeria hepatic tissues, thus leading to its accumulation. The car- Teaching Hospital, Enugu; and University of Port Har- cinogenic activity of 4-hydroxyestradiol could be due to court Teaching Hospital, Port Harcourt. The Institutional its hormonal activity, which in some biological assays has Review Board of University of Pittsburgh and the Ethics been shown to be even higher than the parent hormone. and Research Committees of the Nigerian institutions In addition, 4-hydroxyestradiol can undergo redox cycling approved the study prior to commencement. A total of [7] which results in the formation of free radicals such as 500 study participants comprising 250 women with inci- superoxide and in the generation of reactive semiqui- dent and prevalent breast cancer and 250 age- and institu- none/quinone intermediates that have been shown to tion-matched controls were recruited for the study. damage biological target molecules such as DNA [8]. Women with confirmed breast cancer were recruited dur- ing surgical out-patient clinic visits or in-patient admis- Six polymorphisms of the CYP1B1 gene have been sions while control subjects with non-malignant surgical described in the Caucasian populations, of which four diseases such as road traffic accident and other injuries (n results in amino acid substitutions [3,4]. Two of these = 168), intestinal obstructions (n = 49), appendicitis/pel- amino acid substitutions are located in exon 3, which vic inflammatory disease (26), urolithiasis and urinary encodes the heme-binding domain: codon 432 Val → Leu tract infections (n = 5) and cholelithiasis (n = 2) were and 453 Asn → Ser [4] while two other amino acid substi- recruited from the same hospitals. Exclusion criteria tutions are found in codons 48 Arg → Gly and 119 Ala → include non-confirmation of diagnosis of breast cancer, a Ser in exon 2 [3]. The codon 432 Val → Leu polymor- diagnosis of other malignant diseases, and refusal of phism creates and Eco57I site. Several molecular epidemi- donation of blood samples. ological studies have evaluated the association of polymorphisms in CYP1B1 gene and breast cancer risk in Prior to recruitment, participants signed informed con- various populations, including seven in Caucasian [4,9- sent after detailed explanation of key points of the study 14] and four in Asian populations [15-18]. There is scanty including study objectives, risks and benefits, confidenti- Page 2 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 ality and the rights of participants. Interviewer-adminis- containing genomic DNA and a negative control contain- tered questionnaires were used for data collection; ing everything except DNA were included in the PCR questions were designed to gather demographic history experiment. Five μl of each PCR product, including the including age, sex, religion, occupation, exposure to controls, were verified on a 2% agarose gel to ensure that chemical fertilizers and pesticides, and rearing of domes- the expected 650 bp product was generated. tic animals. In addition, obstetric and gynecological his- tory including age at menarche, age at first full-term Restriction digest for the DNA fragment was carried out pregnancy, parity, breastfeeding, age at menopause (for using Eco57I restriction enzyme. Fifteen μl of the PCR postmenopausal subjects), history of use of hormonal product was digested for 16 h overnight at 37°C with 1 contraceptives and hormone replacement therapy and unit of Eco57I (New England Biolabs). The product of the surgical oophorectomy was obtained. Information about restriction digest was mixed with 10 μl of loading dye and lifestyle habits such as cigarette smoking and alcohol con- verified on a 3% agarose gel (with Ethidium bromide) sumption was also obtained from study participants. electrophoresis in a 1× Tris-Borate-EDTA buffer at 200 V Anthropometric measurements including height, weight, for 60 min. The presence of a G at position 1294 waist and hip circumferences were taken at the end of the (CYP1B1-codon 432) generated a unique 650 bp frag- interview. ment, while the 650 bp fragment was divided into unique 340 bp and 310 bp fragments when position 1294 con- Sample donation and preparation tains a C. The gels were visualized by UV light and the Blood samples were collected at the end of the interview; RFLP gel electrophoresis products were read by two inde- details are reported elsewhere [19,20]; 10 ml of whole pendent persons who were unaware of the identities of blood was collected in one 10 ml K -EDTA vacutainer samples as either cases or controls. tube from each of the study participants and stored in ice packs until it was centrifuged within 10 h of collection RFLP assays employing Eco57I restriction enzyme were and buffy coats collected and stored in 3 ml tubes. All the successful in 228 cases and 226 controls, therefore the samples were stored at -20°C in the various study sites in analysis is restricted to this sample of women. Nigeria and later transferred to the Nigerian coordinating Statistical analysis center at the University of Benin Teaching Hospital in Polar Pack -20 C ice packs for frozen shipments and later Statistical analysis was carried out using the Statistical shipped to University of Pittsburgh in dry ice using Analysis System (SAS) software (Version 8.0). Condi- express services. Samples were stored at -80°C at the Uni- tional logistic regression was used to assess the association versity of Pittsburgh until DNA extraction. between the CYP1B1 genotypes and breast cancer risk in the whole sample. Stratified analyses according to meno- DNA extraction was carried out using QIAamp DNA Mini pausal status were carried out. Relevant risk factors that Kits (for buffy coats) and QIAamp DNA Midi Kits (for were identified as significant predictors of breast cancer blood clots) protocols (QIAGEN Inc. Valencia, CA). The risk were controlled for in the multivariate logistic regres- extracted DNA was stored at 4°C until used for PCR and sion models. RFLP analysis. Results PCR and RFLP analysis Demographic characteristics Genomic DNA from the cases and control subjects were Five hundred participants comprising 250 women with analyzed for the presence of the G to C transversion muta- breast cancer and 250 age- and institution-matched con- tion at codon 432 of the CYP1B1 gene by a PCR-based trols were recruited from four University Teaching Hospi- Restriction Fragment Length Polymorphism (RFLP) assay. tals in Midwestern and Southeastern Nigeria. However, PCR amplification of a 650 bp fragment of the CYP1B1 this report is based on data on 228 cases and 226 control gene, including part of exon 3 that contains the polymor- subjects in whom RFLP polymorphism assays on CYP1B1 phism was carried out using forward primer: TCACTT- gene were successful. Mean age of cases and control sub- GCTTTTCTCTCTCC and reverse primer: jects were similar (46.3 ± 11.72 years and 47.3 ± 12.14 AATTTCAGCTTGCCTCCTG. A 50 μl PCR reaction mixture years respectively). Using univariate logistic regression containing 2 μl of genomic DNA, 5 μl of deoxynucleotide models, the following variables including family history triphosphates, 5 μl each of forward and reverse primers, 5 of breast cancer, education, ever married, age at fullterm μl of 10× buffer, 1.5 μl of MgCl and 0.5 μl of Taq pregnancy (FFTP), parity, duration of breastfeeding, abor- polymerase was placed in a thermalcycler. After denatur- tion, use of hormone contraceptives, waist/hip ratio, and ing for 10 min at 95°C, the DNA was amplified for 35 body mass index (BMI) were found to be significant pre- cycles at 95°C for 60 s, 58°C for 60 s, and 72°C for 60 s, dictors of breast cancer risk. However, only three variables followed by a 7 min extension at 72°C. A positive control including Family history of breast cancer (OR = 11.17, Page 3 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 95% CI 1.37–91.33), age at first fullterm pregnancy frequency of the CYP1B1 (Val/Val), CYP1B1 (Val/Leu) greater than 20 years (OR = 1.32, 95% CI 1.17–3.41) and and CYP1B1 (Leu/Leu) genotypes among cases and con- waist/hip ratio (OR = 1.90, 95% CI 1.18–3.04) were sig- trol subjects, as shown in Table 2. All the three nificant predictors of breast cancer risk in the final multi- homozygous variants were control subjects. ple logistic regression model as shown in Table 1. More details on distribution of anthropometric and reproduc- CYP1B1 genotypes and breast cancer risk All women tive variables and their association with breast cancer are reported elsewhere [21,22]. As shown in Table 2, cases were more likely to harbor the Leu allele than the controls. The heterozygous CYP1B1 Allele and genotype frequencies (Val/Leu) genotype was associated with a significant All women increased risk of breast cancer (Odds ratio [OR] = 1.59, The CYP1B1 (Val) allele was less frequent in cases (0.86) 95% Confidence Interval [CI] 1.01–2.52), compared with compared to control subjects (0.89). The distribution of the homozygous wild type CYP1B1 (Val/Val) genotype. the CYP1B1 genotype is shown in Table 2. The genotype There were very few study subjects with the homozygous frequencies of the CYP1B1 (Val/Val), CYP1B1 (Val/Leu) variant CYP1B1 (Leu/Leu), four among the cases and five and CYP1B1 (Leu/Leu) in the cases were 0.73, 0.25, and among the control subjects; this genotype was not associ- 0.02, respectively while the corresponding frequencies in ated with breast cancer (OR = 0.87, 95% CI 0.23–3.30). the control subjects were 0.81, 0.17, and 0.02, respec- tively. The distribution of CYP1B1 (Val/Leu) alleles in the Adjustment for waist/hip ratio (WHR) slightly attenuated control subjects was in Hardy-Weinberg equilibrium, the risk associated with the CYP1B1 1B1 (Val/Leu) geno- overall and in both premenopausal and postmenopausal type in all women (OR = 1.57, 95% CI 0.99–2.51). The women. risk associated with the CYP1B1 (Leu/Leu) (OR = 0.94, 95% CI 0.24–3.64) and the combined CYP1B1 (Val/Leu) Premenopausal women and CYP1B1 (Leu/Leu) genotypes (OR = 1.51, 95% CI Among 142 premenopausal breast cancer cases and 142 0.96–2.36) remained essentially unchanged. premenopausal control women, the RFLP polymorphism Premenopausal women assays were successful in 125 cases and 129 controls. The CYP1B1 (Val) allele was less frequent among premeno- The heterozygous CYP1B1 (Val/Leu) genotype was associ- pausal cases (0.85) compared to the control subjects ated with a significantly increased risk of premenopausal (0.92). As shown in Table 2, the CYP1B1 (Val/Leu) and breast cancer (OR = 2.00, 95% 1.05–3.81; the risk associ- CYP1B1 (Leu/Leu) genotypes were more common in ated with the homozygous genotype (Leu/Leu) did not cases compared with the control subjects. reach significance (OR = 2.40, 95% CI 0.43–13.38). The risk of premenopausal breast cancer with the hetero- Postmenopausal women zygous CYP1B1 (Val/Leu) and homozygous CYP1B1 Of the 108 postmenopausal breast cancer cases and 108 (Leu/Leu) genotypes combined was 2.04 (95% CI 1.10– postmenopausal control subjects, the PCR-based RFLP 3.78) (Table 2). The risk of premenopausal breast cancer assays were successful in 103 cases and 97 control sub- associated with the CYP1B1 genotypes remained essen- jects. The distribution of the CYP1B1 (Val) and CYP1B1 tially unchanged when WHR was included in the model. (Leu) alleles in postmenopausal breast cancer cases and controls were similar. There were slight differences in the Table 1: Multiple conditional logistic regression comparing cases and controls. Significant demographic predictors of breast cancer risk [Numbers (Percentages (%)], odds ratio (OR), 95% confidence interval (95% CI) Variable Cases Controls OR 95% CI Family history breast Yes 14 (6.00) 1 (0.40) 11.17 1.37, 91.33 Cancer No 214 (94.00) 225 (99.60) 1.00 Age at first fullterm Yes 162 (77.20) 136 (65.07) 1.32 1.17, 3.41 Pregnancy (>20 years) No 48 (22.8) 73 (34.93) 1.00 Waist/hip ratio (>0.90) Yes 147 (64.47) 107 (47.35) 1.90 1.18, 3.04 No 81 (35.53) 119 (52.65) 1.00 Page 4 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 Table 2: Distribution of Cytochrome P4501B1 alleles and genotypes in relation to breast cancer risk Cases Controls OR (95% CI) OR (95% CI)* All women (n = 228) (n = 226) Allele frequencies CYP1B1(Val) 0.86 0.89 CYP1B1(Leu) 0.14 0.11 Genotype frequencies CYP1B1 (Val/Val) 167 (47.85) 182 (52.15) 1.00 CYP1B1 (Val/Leu) 57 (59.38) 39 (40.62) 1.59 (1.01–2.52) 1.57 (0.99–2.51) CYP1B1 (Leu/Leu) 4 (44.44) 5 (55.6) 0.87 (0.23–3.30) 0.94 (0.24–3.64) CYP1B1 (Val/Val) 167 (47.85) 182 (52.15) 1.00 CYP1B1 (Val/Leu) + (Leu/Leu) 61 (58.10) 44 (41.90) 1.51 (0.92–2.35) 1.51 (0.96–2.36) Pre-menopausal women (n = 125) (n = 129) Allele frequencies CYP1B1(Val) 0.85 0.92 CYP1B1(Leu) 0.15 0.08 Genotype frequencies CYP1B1 (Val/Val) 91 (45.50) 109 (54.50) 1.00 CYP1B1 (Val/Leu) 30 (62.50) 18 (37.50) 2.00 (1.05–3.81) 1.97 (1.02–3.81) CYP1B1 (Leu/Leu) 4 (66.67) 2 (33.33) 2.40 (0.43–13.38) 2.64 (0.46–15.23) CYP1B1 (Val/Val) 91 (45.50) 109 (54.50) 1.00 CYP1B1 (Val/Leu) + (Leu/Leu) 34 (62.96) 20 (37.04) 2.04 (1.10–3.78) 2.04 (1.07–3.81) Postmenopausal women (n = 103) (n = 97) Allele frequencies CYP1B1(Val) 0.87 0.86 CYP1B1(Leu) 0.13 0.14 Genotype frequencies CYP1B1 (Val/Val) 76 (51.00) 73 (49.00) 1.00 CYP1B1 (Val/Leu) 27 (56.30) 21 (43.80) 1.24 (0.64–2.38) 1.20 (0.62–2.34) CYP1B1 (Leu/Leu) 0 (0.00) 3 (100.00) ** ** CYP1B1 (Val/Val) 76 (51.00) 73 (49.00) 1.00 CYP1B1 (Val/Leu) + (Leu/Leu) 27 (52.94) 24 (47.06) 1.08 (0.57–2.04) 1.05 (0.55–2.01) * Adjusted for waist/hip ratio (WHR) ** Odds ratios could not be determined due to missing values in some cells Postmenopausal women designed to evaluate the hypothesis that the CYP1B1 There was no association between the CYP1B1 polymor- Val432Leu polymorphisms in the CYP1B1 gene, a key phism and breast cancer in post menopausal women. candidate gene involved in phase I hydroxylation of estro- Harboring at least one CYP1B1 (Leu) allele was not asso- gens (17β-estradiol and estrone) to 4-hydroxy catechols ciated with risk of breast cancer in postmenopausal might contribute to breast cancer risk in Nigerian women. women (OR = 1.08, 95% CI 0.57–2.04). Controlling for WHR did not significantly alter the risk profiles (Table 2). Comparison of our data with reports from other popula- tions indicates wide variation in the distribution of the Discussion CYP1B1 codon 432 Val → Leu polymorphism across dif- Breast cancer is a disease with unique phenotypic mani- ferent populations groups. The frequency of the CYP1B1 festations in different racial/population groups. It has (Val) allele among control subjects in our study (0.89) is been hypothesized that these population-specific charac- closer to the frequency in African-Americans (0.70) [4] teristics of breast cancer may be partly due to differences but much higher than the figures reported in Caucasians in genetic susceptibility to the disease arising from varia- (0.42) [9], Asians in China (0.46) [18], Japan (0.15) [17], tion in the frequency of different polymorphic alleles of and Korea (0.11) [16]. key candidate genes involved in estrogen and xenobiotic metabolism in different populations. Our study was Page 5 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 Our results suggest that harboring one CYP1B1 (Leu) A small hospital-based case-control study involving 59 allele was significantly associated with breast cancer (OR African-American women found no statistically signifi- = 1.59, 95% CI 1.01–2.52). Subgroup analysis based on cant association between the CYP1B1 Val432Leu poly- menopausal status showed that the risk conferred by this morphism and breast cancer risk [4]. Of three studies in polymorphism was essentially restricted to premenopau- mixed U.S. populations [25-27], one [26] reported no sig- sal women in whom the combination of CYP1B1 (Val/ nificant association, while two [25,27] reported an inverse Leu) and CYP1B1 (Leu/Leu) genotypes was associated association between the Val/Val genotype and breast can- with over 2-fold increased risk of breast cancer (OR = cer (OR = 0.4, 95% CI 0.1–1.0 and OR = 0.7, 95% CI 0.6– 2.04, 95% CI 1.10–3.78). This association was not con- 0.9, respectively) and for the Val/Val and Val/Leu geno- firmed in postmenopausal women. The associations were types combined (OR = 0.4, 95% CI 0.1–1.0 and OR = 0.8, not significantly modified by the adjustment of the data 95% CI 0.7–0.9, respectively). Meta-analysis of these stud- for waist/hip ratio (a surrogate measure of etiologically ies in African-American and mixed populations showed relevant obesity) in either premenopausal or postmeno- no overall significant risk associated with the CYP1B1 pausal women, despite the finding of preferential 4- Val432Leu polymorphism in breast cancer susceptibility hydroxylation of estrogens in obese women on high fat in these populations [24]. diet [23]. Meta-analysis of studies on the association between Several other investigators have evaluated the relationship CYP1B1 Val432Leu polymorphism and breast cancer risk between CYP1B1 polymorphisms and breast cancer in dif- failed to demonstrate an overall significant association in ferent populations. There appear to be no significant over- Asian women [24]. Of the four available studies, three all association between the CYP1B1 Val/Leu variant and [15,16,26] found no significant association. Only one breast cancer risk in Caucasian populations in a recent study in the Chinese population [18] reported that, com- meta-analysis [24]. However, a pooled analysis suggests a pared with those with the Val/Val genotype, women with possible association of both the Val/Leu and Val/Val gen- the Leu/Leu genotype had a 2.3-fold (95% CI 1.2–4.5) otypes with breast cancer in Caucasians but no significant elevated risk of breast cancer after adjusting for confound- effect was observed in Asians or African-American subjects ing variables, the positive association between the Leu/ [24]. Among the seven studies in Caucasians, three Leu genotype and breast cancer was more pronounced in reported no association between the CYP1B1 Val432Leu postmenopausal women (OR = 3.1, 95% CI 1.0–9.1) than polymorphism and breast cancer risk [4,10,14], while in premenopausal women (OR = 1.9, 95% CI 0.8–4.3). three reported a risk effect for the valine allele [9,11,13]; one study reported an inverse association between the The differences in breast cancer risk associated with the valine allele and breast cancer [12]. Statistical significance CYP1B1 Val432Leu polymorphism in different popula- for the association between breast cancer and the CYP1B1 tions may be due to several reasons including differences Val/Val polymorphism was reached in two studies in frequency of Val and Leu alleles in different popula- [11,13]. In one of these studies, Listgarten et al. [11] tions, the relatively small sample size of some studies found that harboring the heterozygous Val/Leu genotype [4,11,13,25,26], as well as differences in study designs. was associated with a 2.15-fold increased risk of breast cancer (95% CI 1.31–3.52) while the homozygous The mechanisms through which polymorphisms in mutant (Leu/Leu) conferred a 3.30-fold increased risk CYP1B1 might influence breast cancer risk are not com- (95% CI 1.76–6.19). In the second study of 84 cases and pletely known. CYP1B1 is expressed constitutively in ext- 103 controls among the Turkish population, Kobacas et rahepatic tissues including lung and mammary tissue al. [13] reported an overall association between carriers of [28]. Although other cytochrome P450 enzymes, such as at least one Val allele and breast cancer risk among CYP1A2 and CYP3A4, are involved in hepatic and extrahe- women with body mass index (BMI) > 24 kg/m (OR = patic estrogen hydroxylation, CYP1A1 and CYP1B1 dis- 2.81, 95% CI 1.38–3.74). Although Bailey et al. [4] failed play the highest levels of expression in breast tissue [28]; to demonstrate a significant association between the CYP1B1 exceeds CYP1A1 in its catalytic efficiency as an CYP1B1 Val432Leu polymorphism and breast cancer risk, estradiol (E ) hydroxylase, and differs from CYP1A1 in its they noted that Caucasian patients with the Val/Val geno- main site of catalysis [5,29,30]. CYP1B1 has its primary type had a significantly higher percentage of breast cancer activity at the C-4 position of estradiol (E ), whereas that were positive for estrogen receptors (ERs) or proges- CYP1A1 has its primary activity at the C-2 position. These terone receptors (PRs), suggesting that this polymorphism two metabolites differ greatly in their carcinogenicity. may be functionally important for the expression of these Treatment with 4-OH-E , but not 2-OH-E , induced renal 2 2 steroid receptors. cancer in Syrian hamster [7,31]. Analysis of renal DNA demonstrated that 4-OH-E significantly increased 8- hydroxydeoxyguanosine levels, whereas 2-OH-E did not Page 6 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 cause oxidative DNA damage [32]. Similarly, 4-OH-E logical information. In fact, breast cancer is predomi- induced DNA single-strand breaks whereas 2-OH-E had a nantly a premenopausal disease in Nigerian women [37], negligible effect [33]. Comparison of the corresponding with a disproportionately higher prevalence of hormone catechol estrogen quinones showed that E -3,4-quinone receptor negative breast cancer, estimated at about 76% produced two to three orders of magnitude higher levels [38]. These data, together with the observation of a higher of depurinating adducts than E -2,3-quinone. Signifi- proportion of the CYP1B1 (Val) allele among postmeno- cantly higher 4-OH-E /2-OH-E ratios were observed in pausal women with hormone receptor positive breast can- 2 2 breast tumor tissue than in adjacent normal breast tissue cer [4], and of an association between Nigerian [34]. These findings suggest a causative role of 4-OH cate- premenopausal breast cancer and the CYP1B1 (Leu) allele chol estrogens in carcinogenesis and implicate CYP1B1 as suggest that breast cancer in sub-Saharan African popula- a key player in the process. tions may have a different etiopathogenesis than in Cau- casian or Asian populations. The understanding of To the best of our knowledge, ours is the largest case-con- differences in estrogen and xenobiotic metabolism result- trol study on CYP1B1 Val432Leu polymorphism and ing from polymorphic variants in key candidate genes, breast cancer risk conducted in African populations. and their interaction with environmental exposure has the potential to considerably improve our ability to char- The epidemiologic literature on determinants of breast acterize individual risk of breast cancer and enhance our cancer in sub-Saharan African populations is scanty ability to design individual and population-specific con- despite the evidence that breast cancer is already a public trol and preventive measures. health problem in these developing countries [35,36] and the burden of the disease is likely to increase as women in List of abbreviations used these populations adopt Western diets and sedentary life- CYP1B1: Cytochrome P4501B1 gene; DNA: Deoxyribonu- styles. The use of hospital controls instead of population- cleic acid; PCR: Polymerase chain reaction; SNP: Single based controls might be a source of systematic bias; poor Nucleotide Polymorphism; CYP1A2: Cytochrome research infrastructure including the absence of a popula- P4501A2 gene; CYP3A4: Cytochrome P4503A4 gene; E : tion-based cancer registry and lack of functional commu- 17β-estradiol; 2-OH-E : 2-Hydroxy-Estradiol; 2-OH-E : 4- 2 2 Hydroxy-Estradiol; ER: Estrogen receptor; PR: Progester- nication facilities limited our choice of recruitment for the control subjects. Recruitment of incident and prevalent one receptor; SAS: Statistical Analysis Systems. cases of breast cancer may also be a source of systematic bias as women with rapidly progressive forms of breast Competing interests cancer may have died early, leaving us with a subpopula- The authors declare that they have no competing interests. tion of less aggressive prevalent cases. This is particularly important given the report of an interaction between the Authors' contributions CYP1B1 Val → Leu polymorphism and hormone receptor MNO, CHB, ET, SJG, REF, LHK, participated in conceptu- status noted in Caucasian women [4]. The observed pre- alization, design of the study and preparation of manu- ponderance of hormone receptor positive tumors in indi- script; MNO, ERE, SNCA, JO and EEOU recruited study viduals harboring the Val/Val genotype would result in participants from Nigeria and organized the transfer of selective survival advantage of this genotype. However, biological samples to the University of Pittsburgh; MNO, such an interaction if present in our study population CHB, ET, SJG and JMZ carried out the genetic analysis and would result in underestimation of the breast cancer risk manuscript preparation. associated with the presence of the CYP1B1 (Leu) allele. The non-availability of facilities for hormone receptor Acknowledgements This study was supported by a post-doctoral grant awarded to Michael N. assays during the recruitment of study participants in the Okobia by the U.S. Army Medical and Materiel Command's Breast Cancer Nigerian study sites limited our ability to actually evaluate Research Program (Award Number: DAMD17-02-1-0551). We are grate- the presence of such interaction if any. ful to the staff of the Departments of Surgery of the Nigerian Study Sites including University of Benin Teaching Hospital, Benin City; Nnamdi Conclusion Azikiwe University Teaching Hospital, Nnewi; University of Nigeria Teach- This study has demonstrated a role for the CYP1B1 Val → ing Hospital, Enugu; and the University of Port Harcourt Teaching Hospital, Leu polymorphism in premenopausal breast cancer risk in Port Harcourt, for all their assistance during the recruitment of study par- Nigerian women. This polymorphism might be mediating ticipants. Special thanks to the staff of the Department of Epidemiology, University of Pittsburgh for their invaluable assistance throughout the con- its effect through increased metabolic conversion of estra- duct of this study. diol, the main estrogen in premenopausal women, to 4- hydroxy estradiol and estrogen quinone and semiquinone This article has been published as part of Infectious Agents and Cancer. Vol- intermediates. The results we report in this study need to ume 4 Supplement 1, 2009: Second Annual International African-Caribbean be considered in conjunction with clinical and epidemio- Page 7 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S12 http://www.infectagentscancer.com/content/4/S1/S12 Cancer Consortium Conference. The full contents of the supplement are of breast cancer. Cancer Epidemiol Biomarkers Prev 2000, 9(2):147-150. available online at http://www.infectagentscancer.com/supplements/4/S1. 19. 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