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Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study.

ABSTRACT: INTRODUCTION: Vitamin D receptor (VDR) polymorphisms have been inconsistently associated with breast cancer risk. Whether risk is influenced by polymorphisms in other vitamin D metabolism genes and whether calcium or vitamin D intake modifies risk by genotype have not been evaluated. METHODS: We conducted a nested case-control study within the Cancer Prevention Study II Nutrition Cohort of associations between breast cancer and four VDR single-nucleotide polymorphisms (SNPs), Bsm1,Apa1,Taq1, and Fok1, a poly(A) microsatellite, and associated haplotypes (baTL and BAtS). We also examined one SNP in the 24-hydroxylase gene (CYP24A1) and two in the vitamin D-binding protein (group-specific component [GC]) gene. Participants completed a questionnaire on diet and medical history at baseline in 1992. This study includes 500 postmenopausal breast cancer cases and 500 controls matched by age, race/ethnicity, and date of blood collection. RESULTS: Incident breast cancer was not associated with any genotype examined. However, women with the Bsm1 bb SNP who consumed greater than the median intake of total calcium (> or = 902 mg/day) had lower odds of breast cancer compared to women with the Bb or BB genotype and less than the median calcium intake (odds ratio 0.61, 95% confidence interval 0.38 to 0.96; p(interaction) = 0.01). Similar interactions were observed for Taq1 (T allele) and the poly(A) (LL) repeat. CONCLUSION: We found no overall association between selected vitamin D pathway genes and postmenopausal breast cancer risk. However, certain VDR gene polymorphisms were associated with lower risk in women consuming high levels of calcium, suggesting that dietary factors may modify associations by VDR genotype.

SUBMITTER: McCullough ML

PROVIDER: S-EPMC1851389 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study.

McCullough Marjorie L ML Stevens Victoria L VL Diver William R WR Feigelson Heather S HS Rodriguez Carmen C Bostick Robin M RM Thun Michael J MJ Calle Eugenia E EE

Breast cancer research : BCR 20070101 1

<h4>Introduction</h4>Vitamin D receptor (VDR) polymorphisms have been inconsistently associated with breast cancer risk. Whether risk is influenced by polymorphisms in other vitamin D metabolism genes and whether calcium or vitamin D intake modifies risk by genotype have not been evaluated.<h4>Methods</h4>We conducted a nested case-control study within the Cancer Prevention Study II Nutrition Cohort of associations between breast cancer and four VDR single-nucleotide polymorphisms (SNPs), Bsm1,A ...[more]

PMID: 17244366

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Project description:IntroductionElevated levels of circulating estrogens are linked to breast cancer risk among postmenopausal women but little is known about the importance of estrogen metabolism. A recently developed liquid chromatography tandem mass spectrometry-based method (LC-MS/MS) measuring a panel of 15 estrogen metabolites (EM) has been evaluated in one study, linking high levels of 2-pathway metabolites relative to the parent estrogens to reduced breast cancer risk. We analyzed this panel of EM in a nested case-control study of postmenopausal breast cancer.MethodsBetween 1977 and 1987, 6,915 women provided blood samples to the Columbia Missouri Serum Bank and were followed for incident breast cancer through December 2002. We studied 215 postmenopausal breast cancer cases and 215 matched controls who were postmenopausal and not using exogenous hormones at the time of blood draw. EM were examined individually, grouped by pathway (hydroxylation at the C-2, C-4 or C-16 positions of the steroid ring) and by ratios of the groupings. Logistic regression models controlling for matching and breast cancer risk factors were used to calculate quartile-specific odds ratios (ORs) and 95% CIs.ResultsSignificant elevated risks were not observed for individual EM, except for quartiles of 16-epiestriol (P trend = 0.07). The OR for total EM, the parent estrogens estrone and estradiol, and 2-pathway catechol EM (2-hydroxyestrone and 2-hydroxyestradiol) were elevated but the trends were not statistically significant. Among 2-pathway metabolites, risks for the highest levels of 2-hydroxyestrone-3-methyl ether and 2-methoxyestradiol were reduced; ORs for women in the highest versus lowest quartiles were 0.57 (95% CI = 0.33 to 0.99) and 0.53 (95% CI = 0.30 to 0.96), respectively. Overall, women with higher levels of 2-pathway EM had a reduced risk of breast cancer, which remained after accounting for levels of parent EM, 4-pathway EM and 16-pathway EM (all trends, P <0.11).ConclusionsWomen with more extensive hydroxylation along the 2-pathway may have a reduced risk of postmenopausal breast cancer. Further studies are needed to clarify the risks for specific EM and complex patterns of estrogen metabolism. This will require aggregation of EM results from several studies.

Project description:IntroductionVitamin D receptor (VDR) genotypes may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D, but epidemiological studies have been inconsistent. Effect modification by serum 25-hydroxyvitamin D (25 [OH]D), the biomarker for vitamin D status in humans, has rarely been examined.MethodsWe assessed the effects of two frequently analyzed polymorphisms (FokI and TaqI) and two potentially functional variants (VDR-5132 and Cdx2) in the VDR gene, which thus far have not been analyzed with respect to breast cancer risk, on postmenopausal breast cancer risk in a population-based, case-control study including 1,408 patients (cases) and 2,612 control individuals (controls) matched for year of birth. Odds ratios (ORs) for breast cancer adjusted for potential confounders were calculated for genotypes and estimated haplotypes.ResultsNo differences in serum 25(OD)D concentrations by VDR genotype were observed. None of the analyzed polymorphisms was associated with overall risk for postmenopausal breast cancer. However, the TaqI polymorphism was associated with a significantly increased risk for oestrogen receptor positive tumours (OR = 1.18, 95% confidence interval [CI] = 1.00 to 1.38, comparing t allele carriers with noncarriers) but not for oestrogen receptor negative tumours (OR = 0.88, 95% CI = 0.69 to 1.13; P for interaction = 0.04). Haplotype analysis revealed the haplotype FtCA (FokI F, TaqI t, VDR-5132 C, Cdx2 A), which contains the TaqI t allele, to be associated with a significantly greater breast cancer risk as compared with the most frequent haplotype FTCG (OR = 1.43, 95% CI = 1.00 to 2.05). No significant interaction between VDR genotypes or haplotypes and 25(OH)D was observed.ConclusionOur results support potential effects of VDR polymorphisms on postmenopausal breast cancer risk and possible differential effects of receptor status of the tumour. However, further studies focusing on the influence of polymorphisms and haplotypes on VDR functionality, activity and concentration are needed.

Project description:BACKGROUND:Brominated flame retardants (BFRs) are lipophilic substances with endocrine-disrupting properties. To date, only few investigations, mainly retrospective case-control studies, have explored the link between internal levels of BFRs and the risk of breast cancer, leading to conflicting results. We investigated the associations between plasma concentrations of two main groups of BFRs, PBDEs (pentabromodiphenyl ethers) and PBBs (polybrominated biphenyls), and the risk of breast cancer in a nested case-control study. METHODS:A total of 197 incident breast cancer cases and 197 controls with a blood sample collected in 1994-1999 were included. Plasma levels of PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, BDE153, BDE-154) and of PBB-153 were measured by gas chromatography coupled to high-resolution mass spectrometry. Conditional logistic regression models, adjusted for potential confounders, were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS:Women were aged 56?years on average at blood draw. All cases, except for one, were diagnosed after menopause, with an average age at diagnosis of 68?years. Overall, we found no evidence of an association between plasma levels of PBDEs and PBB-153 and postmenopausal breast cancer risk (log-concentrations of BFRs yielding non-statistically significant ORs of 0.87 to 1.07). The analysis showed a non-linear inverse association for BDE-100 and BDE-153 and postmenopausal breast cancer risk; nevertheless, these findings were statistically significant only when the exposure was modeled as ng/L plasma (third vs. first quintile: OR?=?0.42, 95%CI?=?0.19-0.93 and OR?=?0.42, 95%CI?=?0.18-0.98, respectively) and not when modeled as ng/gr of lipids (OR?=?0.58, 95%CI?=?0.27-1.25 and OR?=?0.53, 95%CI?=?0.25-1.17). These results were unchanged in stratified analyses by tumor hormone receptor expression or body mass index. CONCLUSIONS:Our results suggest no clear association between internal levels of PBDEs and PBB-153 and the risk of breast cancer in postmenopausal women. However, these findings need to be carefully interpreted, taking into account limitations due to the limited number of women included in the study, the lack of information concerning genetic susceptibility of cases, and the unavailability of exposure assessment during critical windows of susceptibility for breast cancer. More studies are warranted to further investigate the relationships between PBDE and PBB exposure and breast cancer risk.

Project description:Breast cancer is the most prevalent cancer in females worldwide. Studies evaluating the blood vitamins and minerals status in the breast cancer etiology are limited, and the results are inconclusive. This study analyzed the association between serum vitamin-mineral profiles (V-MPs) and breast cancer (BC) risk with including dietary patterns (DPs) and the use of supplements. This case-control study involved 420 women aged 40-79 years from north-eastern Poland, including 190 newly diagnosed breast cancer cases. The fasting serum concentrations of vitamins (folate, cobalamin, 25(OH) vitamin D) and minerals (iron, calcium, magnesium) were measured in 129 post-menopausal women, including 82 controls and 47 cases. Three V-MPs were derived with a Principal Component Analysis (PCA). A logistic regression analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (95% CI) of the breast cancer risk associated with serum V-MPs and serum levels of single biomarkers. The risk of BC was lower by 88% (OR: 0.12; 95% Cl: 0.02-0.88; p < 0.05) in the upper tertile of the serum 'Iron-Calcium' profile compared to the bottom tertile, lower by 67% (OR: 0.33; 95% Cl: 0.11-0.97; p < 0.05) at the level of serum 25(OH) vitamin D ?24.6 ng/mL and lower by 68% (OR: 0.32; 95% Cl: 0.11-0.91; p < 0.05) at the level of serum calcium ?9.6 mg/dL. There was an inverse association of the serum 'Magnesium' profile or serum level of iron with the risk of BC, which disappeared after adjustment for the set of confounders accounted for: age, body mass index (BMI), socioeconomic status, overall physical activity, smoking status, age at menarche, number of full-term pregnancies, oral contraceptive use, hormone-replacement therapy use, family history of breast cancer, vitamin/mineral supplement use, the molecular subtype of breast cancer, and dietary patterns. No significant association was found between BC risk and the serum 'Folate-Cobalamin-Vitamin D' profile or serum folate, cobalamin or magnesium considered separately. These findings highlight that a higher-normal serum level of both iron and calcium, considered together as the serum profile, as well as a higher-normal serum level of calcium, considered separately, and a slightly below the normal range of serum vitamin D level may protect against breast cancer among postmenopausal women, independent of dietary patterns or the use of vitamin/mineral supplements. Therefore, the maintenance of the adequate status of vitamins and minerals and the regular monitoring of their blood markers should be included in breast cancer prevention.

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Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study.

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Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study.

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