This study of female breast cancer patients had two aims: first, to evaluate the risk of ER- or PR- tumors associated with polymorphisms in specific UGT and SULT genes, and second, to investigate whether plasma sex hormone concentrations varied within genotypes of these same genes. To our knowledge this is the first study to investigate the association between polymorphisms in the UGT2B4, UGT2B7, and UGT2B15 genes and risk of an ER- or PR- breast tumor.
There is increasing evidence that hormones are important in the development of hormone-dependent and hormone-independent breast cancer tumors [37
]. Women with ER-
tumors have a worse prognosis and fewer treatment modalities are available. We observed a reduced risk of an ER-
tumor in patients with the UGT1A1
genotype, and indications towards risk reduction with variants of UGT2B15
. The association between breast tumor ER status and the number of TA repeats in the UGT1A1
promoter region has previously been examined in a case-control study of 200 African-American women with breast cancer [14
]. In that study, premenopausal women with (TA)7
'low-activity' alleles seemed to be at higher risk for an ER-
tumor than women with (TA)5
'high-activity' alleles (OR = 2.1, 95% CI 1.0–4.2) [14
]. This elevated risk did not extend to postmenopausal women (OR = 0.8, 95% CI 0.3–1.9), which is consistent with our results among a predominantly postmenopausal population. Our finding of a somewhat reduced risk of an ER-
tumor in women with the SULT1A1
Arg/His and His/His genotypes is consistent with the results of a study of 337 breast cancer patients by Nowell and colleagues [57
]. Given that the hormonal milieu seems important for the development of both hormone-dependent and hormone-independent mammary tumors, our study, in conjunction with others, provides evidence that genotypes relevant to the metabolism and excretion of sex hormones might affect that milieu.
In a substudy of postmenopausal women at least 2 years after diagnosis, we observed that plasma estradiol concentrations varied by UGT1A1
genotypes. The UGT1A1
gene is involved in the glucuronidation of several sex hormones, including 17β-estradiol [9
]. Our finding that breast cancer patients homozygous for the UGT1A1
allele seemed to have increased concentrations of estradiol is consistent with the observation that the variant allele has lower transcriptional activity in vitro
than the wild-type (TA)6
]. However, a study of 274 healthy postmenopausal women in the Nurses' Health Study found that neither estrone nor estradiol concentration varied depending on UGT1A1
]. Our study was restricted to women with breast cancer, the majority of whom were on tamoxifen therapy, which alters estrogen levels, perhaps independently of these genetic factors. Our findings should therefore be confirmed in additional populations of breast cancer patients and healthy controls, to clarify the relationship between the UGT1A1
polymorphism and estradiol concentrations in both healthy women and those with breast cancer.
Our finding that concentrations of estradiol were higher in women with the UGT2B15
allele is surprising, given that the UGT2B15 protein is not known to glucuronidate estradiol [18
]. Further, we did not observe that circulating testosterone concentrations varied greatly by UGT2B15
genotype, despite the fact that UGT2B15 is known to glucuronidate testosterone [18
]. However, this might be explained by the much higher glucuronidation activity of UGT2B17 for testosterone than that of UGT2B15 [18
]. Also surprising was the finding that the SULT1A1
His/His genotype was associated with elevated testosterone concentrations, given that SULT1A1 does not seem to conjugate testosterone [32
]. It is possible that the observed associations between sex hormone concentrations and polymorphisms in UGT2B15
in breast cancer patients are valid. However, they should be viewed as possibly attributable to chance, because there are conflicting biochemical data reported in the literature.
With regard to the UGT2B4
polymorphisms, there was relatively little biochemical evidence to support an a priori
hypothesis about an association between these polymorphisms and circulating sex hormone concentrations or tumor receptor status. We therefore considered these analyses to be 'hypothesis generating', in which any observed association might elucidate the potential functional relevance of these polymorphisms in vivo
. We did not find evidence that these polymorphisms were associated with sex hormone concentrations or the risk of an ER-
breast cancer tumor. Our findings therefore support in vitro
data in which these sequence variations did not seem to alter enzyme function [10
Because genetic factors that might influence circulating sex hormone concentrations in breast cancer patients could influence response to treatment, it is important to understand these associations in breast cancer patients. The results of this study might serve as a starting point for the formation and testing of additional hypotheses regarding the potential association between polymorphisms in the UGT2B4, UGT2B7, and UGT2B15 genes and serum hormone concentrations or hormone receptor status. One strength of the study is the investigation of several genetic polymorphisms in genes relevant to sex hormone excretion or regulation and the measurement of three sex hormones.
However, this study has several limitations. The small size limited the statistical power in many of the analyses and prohibited the evaluation of combined genotype effects. Additionally, the coefficients of variation for the estrone and estradiol assays were somewhat high, possibly preventing us from detecting an association. Another limitation is that we examined polymorphisms in only five genes whose protein products participate in sex hormone regulation; additional proteins involved in regulatory mechanisms that contribute to sex hormone concentrations in vivo could not be considered as part of the study. As with any genetic association study, the results must be interpreted in the light of the possibility that observed associations might be due to linkage disequilibrium between the examined polymorphism and a functional polymorphism that is the true cause of the observed difference. Finally, because this study involved mostly overweight women with breast cancer, most of whom were taking tamoxifen at the time of the study, the observed associations between UGT and SULT genotypes and circulating hormone levels might not be generalizable to healthy women.