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Carcinogenesis Advance Access originally published online on April 13, 2007
Carcinogenesis 2007 28(10):2139-2142; doi:10.1093/carcin/bgm087
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association between CYP3A4 genotype and risk of endometrial cancer following tamoxifen use

William Chu, Anthony Fyles, Edward M. Sellers2, David R. McCready3, Joan Murphy4, Tuya Pal5 and Steven A. Narod6,*

Department of Radiation Oncology, Princess Margaret Hospital–University Health Network, Toronto, Ontario, Canada
1 Department of Medicine, Pharmacology and Psychiatry, University of Toronto, Toronto, Ontario M5G 2M9, Canada
2 Ventana Clinical Research Corporation, Toronto, Ontario M5T 3A9, Canada
3 Department of Surgical Oncology
4 Department of Gynecologic Oncology, Princess Margaret Hospital–University Health Network, Toronto, Ontario M5G 2M9, Canada
5 Department of Interdisciplinary Oncology, University of South Florida, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
6 Center for Research in Women's Health, Women's College Hospital, Toronto, Ontario, Canada

* To whom correspondence should be addressed. Tel: +1 416 351 3765; Fax: +1 416 351 3767 Email: steven.narod{at}wchospital.ca


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Tamoxifen is a selective estrogen receptor modulator that is used to treat and to prevent breast cancer; however, its use is associated with an increased risk of endometrial cancer. Tamoxifen is metabolized by various cytochrome P450 (CYP) enzymes, but predominantly by CYP3A4. In this study, we examined whether a genetic variant of the CYP3A4 gene, CYP3A4*1B, influences endometrial cancer risk—alone and when associated with tamoxifen exposure. We conducted a case–control study on 566 endometrial cancer cases and 964 ethnically matched controls. The variant CYP3A4 allele was present in 6% of the controls and 9% of the endometrial cancer patients (OR = 1.6, 95% CI = 1.1–2.3, P = 0.02). The allele was more common in women with endometrial cancer who had been treated with tamoxifen for breast cancer (16%). Women who carried the CYP3A4*1B allele had ~3-fold increase in the risk of developing endometrial cancer following tamoxifen treatment, compared with women who did not take tamoxifen (P = 0.004). These findings suggest that a subgroup of breast cancer patients who carry the CYP3A4*1B allele and take tamoxifen may be at increased risk of developing endometrial cancer.

Abbreviations: CYP, cytochrome P450; {alpha}-OHT, {alpha}-hydroxytamoxifen; 4-OHT, 4-hydroxytamoxifen; N-DDMT, N-didesmethyltamoxifen; N-DMT, N-desmethyltamoxifen


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Tamoxifen is a selective estrogen receptor modulator that has been shown to reduce recurrence, contralateral disease and mortality in women with estrogen receptor-positive breast cancer (1). Tamoxifen also decreases the risk of ipsilateral invasive breast cancer among women with ductal carcinoma in situ (2), and is used in the chemoprevention of breast cancer. In the National Surgical Breast and Bowel Project (NSABP) P-1 breast cancer prevention trial, tamoxifen reduced the incidence of invasive and non-invasive breast cancer by 57 and 63%, respectively (3). Although a large number of women could potentially benefit from tamoxifen, its widespread use to date in the preventive setting has been limited because of concern over side effects. In particular, tamoxifen has been shown to increase the risk of endometrial cancer by ~3-fold (3–12), although the absolute risk of endometrial cancer among tamoxifen users is small. However, it is possible that all women are not equally at risk for endometrial cancer following tamoxifen use. The metabolism of tamoxifen, which may determine the efficacy and toxicity of the drug, varies considerably between individuals. For example, polymorphic variants in genes that encode for tamoxifen-metabolizing enzymes may be associated with the risk of tamoxifen-related side effects, including endometrial cancer.

Tamoxifen metabolism is a complex process mediated by the cytochrome P450 (CYP) family of enzymes. CYP3A4 is the most abundantly expressed CYP enzyme in the liver (13–15), and is the key enzyme involved in the biotransformation of tamoxifen to its primary metabolites: N-desmethyltamoxifen (N-DMT) (16–20), 4-hydroxytamoxifen (4-OHT) (17–21) and {alpha}-hydroxytamoxifen ({alpha}-OHT), which is believed to be a genotoxic metabolite (19,20,22). CYP2D6 further converts N-DMT to endoxifen (20,23–26). Both 4-OHT and endoxifen are the active metabolites responsible for the anti-estrogenic effect of tamoxifen. They possess a high affinity for estrogen receptors, and are more potent than tamoxifen in suppressing estrogen-dependent cell growth and gene expression (20,23,24,26–29). The CYP3A subfamily also plays a dominant role in the secondary transformation of these primary metabolites. Because CYP3A4 is also expressed in the human endometrium (30–32), intra- and extra-hepatic metabolism of tamoxifen may both contribute to its activity and toxicity.

A genetic variant, CYP3A4*1B, has previously been identified within the P450NF nifedipine-specific element, located in the upstream transcriptional regulatory region of CYP3A4 (33). CYP3A4*1B was found to be associated with a higher stage and grade of prostate cancer (33,34) and with more aggressive disease (35). In men with benign prostatic hyperplasia, CYP3A4*1B is a risk factor for developing prostate cancer (36,37). Since CYP3A4 is involved in hormone metabolism, we investigated the putative link between CYP3A4 and tamoxifen-mediated endometrial cancer. The purpose of this study is to determine whether CYP3A4*1B is a risk factor for endometrial cancer and to establish whether or not there is an interaction between CYP3A4 genotype, tamoxifen use and endometrial cancer risk.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Endometrial cancer cases
Women with endometrial cancer who were treated at the University Health Network, Princess Margaret Hospital, Toronto, from 1996 to 2000 were eligible for the study. Patients were identified through the medical records of the hospital registry. The registry provided the name of the patient, the year and age of diagnosis, the pathologic confirmation of cancer and the name of the treating physician to the study team. Permission to contact the patients was obtained from the treating physician. Details regarding past medical history, reproductive history, family history and history of hormone and tamoxifen use were collected by questionnaire for all study subjects. Blood samples were collected for DNA analysis. In addition, to enrich the sample for women with a potential past history of tamoxifen use, we included women with endometrial cancer and a past history of breast cancer who were treated at other hospitals in Ontario. Women with pathologically verified endometrial cancer diagnosed between 1 July 1977 and 1 July 2000 and with a past history of breast cancer were identified through the Ontario Cancer Registry and were also invited to participate. The Registry records information on all cancers in an individual and it was therefore possible to select women with multiple primary cancers. These women were requested to participate through their treating physicians. To minimize the potential effect of ethnic variation on the association between CYP3A4 and endometrial cancer, the study was restricted to white women. Written consent was obtained for all patients prior to study participation.

Controls
Controls were healthy pre-menopausal and post-menopausal white women who volunteered to participate in a research program designed to study the effect of genetic variation on hormone levels at the Center for Research in Women's Health in Toronto. These control women had no past history of cancer and were unselected for family history of cancer. Blood samples were collected on these women from 1997 to 2002. Written consent was obtained prior to study participation.

CYP3A4 genotype analysis
Genomic DNA was extracted from 30 ml of whole blood collected from the study subjects using Puregene DNA extraction kits. The CYP3A4*1B polymorphism (Pr-392 A -> G, rs2740574) was analyzed in all cases and controls using a PCR-based method as described previously by Jernstrom et al. (38). CYP3A4 genotype was confirmed by direct DNA sequencing (GE Life Sciences, London, UK and Healthcare, formerly Amersham Life Sciences) for all heterozygous and homozygous variant samples, as well as a random selection of wild-type samples.

Statistical analysis
The OR for endometrial cancer associated with CYP3A4*1B was generated by comparing the endometrial cancer cases with the healthy controls. Statistical significance and 95% confidence limits were determined by the chi-squared test.

Tamoxifen metabolite analysis
To study the association between CYP3A4 genotypes and tamoxifen metabolite levels in plasma, a sample of women under active tamoxifen treatment for breast cancer at the Princess Margaret Hospital was recruited. These women had all been diagnosed with node-negative breast cancer and were taking 20 mg of tamoxifen daily at the date of the blood draw. Written consent was obtained prior to study participation. DNA samples were analyzed for CYP3A4 genotypes as described previously. The CYP3A4*1B allele is relatively rare (6% of individuals) and therefore, a sample of individuals with and without the variant allele was selected for tamoxifen metabolite analysis. A total of 23 carriers of CYP3A4*1B were identified from the breast cancer patients. For each of these, two wild-type individuals were matched for the date of breast cancer diagnosis (within 1 year) and for date of birth (within 3 years). The plasma from these patients was analyzed for levels of tamoxifen, 4-OHT, N-DMT and N-didesmethyltamoxifen (N-DDMT) according to the methods described by Fried et al. (39) and Poon et al. (40). The mean metabolite levels and ratios were compared between the two groups to determine whether genotype correlated with differences in the metabolism of tamoxifen into its metabolites. Statistical significance was determined by a two-tailed t-test assuming unequal variances.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
The CYP3A4 variant allele, CYP3A4*1B, was present in 61 of the 964 (6.3%) healthy white controls. This result is consistent with previous determinations of CYP3A4*1B allele frequency (3.6–9.6%) in similar populations (41). We analyzed a total of 566 endometrial cancer cases, including 126 cases with a past history of breast cancer (representing 22.3% of the total number of cases). The CYP3A4*1B allele was present in 54 of the 566 (9.5%) endometrial cancer cases (OR = 1.6, 95% CI = 1.1–2.3, P = 0.02) (Table I). CYP3A4*1B was present in 9.1% of the 440 cases with no previous history of breast cancer and in 11.1% of the 126 cases with a past history of breast cancer. Fifty percent of the women with a previous history of breast cancer had received tamoxifen in the past. Among the tamoxifen-treated women, the variant allele was present in 15.9% of the 63 cases. Compared with healthy controls, this is equivalent to an OR of 2.8 (P = 0.004). Among women with a past history of breast cancer but who did not take tamoxifen, no association with CYP3A4 genotype was seen (Table I). There were no homozygous variant individuals in the study, either in cases or controls.


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  		Table I. Association between CYP3A4*1B allele and endometrial cancer

 
To determine whether a relationship exists between the presence of the CYP3A4*1B allele and the plasma levels of various tamoxifen metabolites, we also studied 68 women with lymph node-negative breast cancer who were undergoing treatment with tamoxifen. We measured the levels of tamoxifen, 4-OHT, N-DMT and N-DDMT in the plasma of these patients and compared the mean metabolite levels and metabolic ratios between those who carried the CYP3A4*1B allele and those who carried wild-type alleles. No differences in the levels of tamoxifen, 4-OHT, N-DMT and N-DDMT metabolite levels were found between CYP3A4*1B carriers and wild-type individuals (Table II).


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  		Table II. Mean (range) tamoxifen metabolite levels by CYP3A4 genotype

 

   Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The risk of endometrial cancer with tamoxifen use is well established (3–12). Tamoxifen is metabolized by various CYP enzymes, predominantly by CYP3A4; therefore, we hypothesized that genetic variants of this gene may be associated with different risks of endometrial cancer development. To date, >78 DNA sequence polymorphisms of CYP3A4 are known (41). The genotype and allelic frequency of CYP3A4*1B is the most extensively studied. We found CYP3A4*1B to be present in 6.3% of our population-based controls, and this is in agreement with an allelic frequency of 3.6–9.6% observed in Caucasians across 16 studies (41). We found that women who carry CYP3A4*1B are at ~3-fold risk of developing endometrial cancer. However, our sample size is relatively small and these results need to be confirmed. The biologic basis for the development of endometrial cancer is hypothesized to be the result of the estrogenic stimulation of the endometrium leading to hyperplasia and malignant transformation or the genotoxic effect of tamoxifen metabolites (summarized in Figure 1).


Figure 1
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  		Fig. 1. Biotransformation of tamoxifen and effects of tamoxifen metabolites. The major metabolic pathways and predominate CYPs involved are highlighted in bold.

 
Several studies have demonstrated that CYP3A4 is the dominant enzyme in the biotransformation of tamoxifen to {alpha}-OHT (19,20,22) and catalyzes the irreversible binding of tamoxifen to DNA (22). Hydroxylation at the {alpha}-position activates tamoxifen, resulting in a resonance-stabilized electrophilic carbocation that is capable of reacting with DNA and forming DNA adducts (42–44). Phase II sulfonation of {alpha}-OHT results in a sulfate ester that is significantly more reactive than {alpha}-OHT itself (45). While DNA adduct formation is a necessary event in the mechanism of action of a genotoxic carcinogen, the formation of tamoxifen–DNA adducts in endometrial carcinogenesis remains controversial because detecting these DNA adducts in the human endometrium is variable (46–51). The expression of CYP3A4 in the human endometrium (30), and the formation of DNA adducts in human endometrial explant cultures following exposure to {alpha}-OHT (52), suggests that the local metabolism of tamoxifen in this target tissue probably contributes to its toxicity.

CYP3A4*1B has not been found to be associated with breast cancer per se, but there are few studies in this regard. In a large case–control study, which contained 951 breast cancer cases and 500 controls, Spurdle et al. (55) found no association between CYP3A4*1B and breast cancer risk (OR = 0.9, 95% CI = 0.5–1.3).

The functional significance of the CYP3A4*1B allele is yet to be determined. In vitro and in vivo studies have yielded conflicting results. Amirimani et al. (53,54) reported that CYP3A4*1B was associated with increased transcriptional activity in CYP3A4-luciferase gene reporter constructs due to lower binding affinity of a transcriptional repressor compared with wild type. However, Spurdle et al. (55) found no effect of the polymorphism on transcriptional activity in their CYP3A4-luciferase gene reporter assays. Conversely, lower nuclear protein-binding affinity and lower transcriptional activity have been reported in a promoter containing the CYP3A4*1B allele when compared with a wild-type promoter (56). Additional in vitro studies have found no relationship between CYP3A4*1B and nifedipine and erythromycin metabolism (57,58) or testosterone hydroxylase activity (59,60). Results from in vivo studies analyzing nifedipine, erythromycin and midazolam metabolism have been equivocal (60,61). Currently, no major polymorphic variant in CYP3A4 has been significantly linked to CYP3A4 activity (41). These studies have only examined hepatic and human liver microsome expression and function of CYP3A4, and do not account for extra-hepatic CYP3A4 activity.

In vitro studies have demonstrated that several other CYP enzymes are also involved in tamoxifen metabolism (19,20) (Figure 1). Of these, CYP2D6 and CYP3A5 play an important role in converting tamoxifen to N-DMT and endoxifen. In particular, CYP2D6 genotype and CYP2D6 inhibitors have been shown to affect circulating endoxifen levels (23,25). Recently, explant cultures of human endometrium demonstrated the role of CYPs 3A4, 2C9, 1A1 and 1B1 in the biotransformation of tamoxifen (32). Interestingly, immunohistochemical and immunoblot analyses confirmed the expression of CYP3A4 in these cultures, but did not detect CYP2D6. We did not find an association between CYP3A4 genotype and 4-OHT, N-DMT and N-DDMT levels in this study. Therefore, the biological basis of the observed association is not clear. The metabolites that we analyzed may or may not be central in carcinogenesis. Examination of {alpha}-OHT and endoxifen levels in our series may be useful, but these assays were not available to us. We were also limited by a relatively small sample size and it is also possible that ours is a chance finding. Further studies to determine the interaction between CYP3A4, CYP3A5 and CYP2D6 genotypes and the impact of genotype on tissue-specific protein expression and bioactivation of tamoxifen would be informative.

In conclusion, we have shown that women who carry the CYP3A4*1B allele appear to be at increased risk for developing tamoxifen-related endometrial cancer. Through the use of the Ontario Cancer Registry, we were able to identify 63 women with endometrial cancer who had taken tamoxifen in the past. Nevertheless, this sample size is small and it is important that these findings be confirmed in other studies. If confirmed, our results may be relevant in the decision of whether or not to use tamoxifen for the chemoprevention of breast cancer or for the treatment of invasive disease. They may also help to identify a subgroup of tamoxifen users who may be candidates for increased endometrial surveillance or prophylactic hysterectomy.


   Acknowledgments
 
Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received August 15, 2006; revised March 29, 2007; accepted April 2, 2007.


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