BACKGROUND: Vitamin D status, determined on the basis of 25-hydroxyvitamin D 25(OH)D concentrations, is associated with the risk of several diseases. Vitamin D binding protein (DBP) is the major ...carrier of vitamin D and its metabolites, but the role of DBP single nucleotide polymorphisms (SNPs) on 25(OH)D concentrations is unclear. OBJECTIVE: The objective was to evaluate the association of 2 DBP gene SNPs with 25(OH)D concentrations and explore whether such association varies according to the amount of vitamin D that needs to be transported. DESIGN: This cross-sectional study included 741 premenopausal white women, mostly of French descent. Plasma 25(OH)D concentrations were measured by radioimmunoassay. DBP-1 (rs7041) and DBP-2 (rs4588) were genotyped with a Sequenom MassArray platform. Associations and interactions were modeled by using multivariate linear regression. RESULTS: DBP-1 and DBP-2 SNPs were in strong linkage disequilibrium and were both associated with 25(OH)D concentrations. An additional copy of the rare allele of DBP-1 or DBP-2 was associated with lower 25(OH)D concentrations (β = -3.29, P for trend = 0.0003; β = -4.22, P for trend < 0.0001, respectively). These DBP polymorphisms explained as much of the variation in circulating 25(OH)D as did total vitamin D intake (r² = 1.3% for DBP-1, r² = 2.0% for DBP-2, and r² less-than or equal to 1.2% for vitamin D intake). CONCLUSION: Circulating 25(OH)D concentrations in premenopausal women are strongly related to DBP polymorphisms. Whether DBP rare allele carriers have a different risk of vitamin D-related diseases and whether such carriers can benefit more or less from dietary interventions, vitamin D supplementation, or sun exposure need to be clarified.
The insulin-like growth factor (IGF) pathway is believed to play a role in carcinogenesis of the mammary gland. Single nucleotide
polymorphisms (SNPs) of IGF-I, IGF-binding protein-3 ( IGFBP-3 ), IGF ...receptor 1, insulin receptor substrate 1 , and phosphoinositide-3-kinase, catalytic, β polypeptide genes, which are members of the IGF pathway, have been associated with risk of common cancers, breast density, and/or IGF
levels but results remain inconclusive. Thus, we evaluated the association of 11 targeted IGF pathway SNPs with circulating
IGF levels and mammographic breast density. Among 741 white premenopausal women, blood samples were collected at time of screening
mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Percent and absolute breast density were estimated
using a computer-assisted method. Multivariate linear models were used to examine the associations. Women carrying increasing
number of copies of the rare allele of IGF-I rs1520220 and rs6220 SNPs had increased percent breast density ( P trend = 0.04 and 0.06, respectively). Carriers of increasing number of copies of the rare allele of phosphoinositide-3-kinase, catalytic, β polypeptide rs361072 SNP had decreased percent ( P trend = 0.04) and absolute ( P trend = 0.02) breast density. An association of insulin receptor substrate 1 rs1801278 SNP with absolute density ( P trend = 0.03) was also observed. All four IGFBP-3 SNPs (including rs2854744) were associated with IGF-I and IGFBP-3 levels. This study shows that several components of the
IGF pathway are associated with breast density or IGF levels. Our findings provide additional support for the idea that several
components of the IGF pathway may affect breast cancer risk and that this effect on breast cancer development may be mediated,
at least in part, through its influence on the morphogenesis of breast tissue. (Cancer Epidemiol Biomarkers Prev 2008;17(4):880–8)
Some studies have suggested that insulin-like growth factor (IGF) pathway is related to premenopausal breast density, one
of the strongest known breast cancer risk factors. This study was designed ...specifically to test the hypothesis that higher
levels of IGF-I and lower levels of IGF-binding protein (IGFBP)-3 are associated with high mammographic breast density among
premenopausal but not among postmenopausal women. A total of 783 premenopausal and 791 postmenopausal healthy women were recruited
during screening mammography examinations. Blood samples were collected at the time of mammography, and plasma IGF-I and IGFBP-3
levels were measured by ELISA. Mammographic breast density was estimated using a computer-assisted method. Spearman's partial
correlation coefficients ( r s ) were used to evaluate the associations. Adjusted mean breast density was assessed by joint levels of IGF-I and IGFBP-3 using
generalized linear models. Among premenopausal women, high levels of IGF-I and low levels of IGFBP-3 were independently correlated
with high breast density ( r s = 0.083; P = 0.021 and r s = −0.124; P = 0.0005, respectively). Correlation of IGF-I with breast density was stronger among women in the lowest tertile of IGFBP-3
than among those in the highest tertile of IGFBP-3 ( r s = 0.138; P = 0.027 and r s = −0.039; P = 0.530, respectively). In contrast, the correlation of IGFBP-3 with breast density was stronger among women in the highest
tertile of IGF-I than among those in the lowest tertile of IGF-I ( r s = −0.150; P = 0.016 and r s = −0.008; P = 0.904, respectively). Women in the combined top tertile of IGF-I and bottom tertile of IGFBP-3 had higher mean breast density
than those in the combined bottom tertile of IGF-I and top tertile of IGFBP-3 (53.8% versus 40.9%; P = 0.014). No significant association was observed among postmenopausal women. Our findings confirm that IGF-I and IGFBP-3
are associated with breast density among premenopausal women. They provide additional support for the idea that, among premenopausal
women, these growth factors may affect breast cancer risk, at least in part, through their influence on breast tissue morphology
as reflected on mammogram.
Vitamin D and calcium are being evaluated as potential breast cancer prevention agents. This study reports on the relation
of dietary vitamin D and calcium to mammographic breast densities, one of ...the strongest breast cancer risk factors. Participants
were women ages 40 to 60 years who had had a screening mammogram in Rhode Island and eastern Massachusetts (1989–1990). Diet
was assessed by semiquantitative food frequency questionnaire, and the percentage of the breast showing densities was estimated
visually by a single observer without information on subjects. Multivariate logistic regression was used to compare dietary
intakes of vitamin D and calcium between women classified as having few densities (≤30% of the breast with density, n = 287) and extensive densities (≥70% of the breast with density, n = 256). For categories of increasing vitamin D intake (<50, 50–99, 100–199, and ≥200 IU/d), adjusted odds ratios (OR) for
extensive densities were 1.00 (reference), 0.51, 0.37, and 0.24, respectively ( P for trend = 0.0005). For increasing calcium intake (<500, 500–749, 750–999, and ≥1,000 mg/d), adjusted ORs were 1.00 (reference),
0.63, 0.25, and 0.24, respectively ( P for trend = 0.0006). Combination of higher intakes of vitamin D and calcium (≥100 IU/d and ≥750 mg/d, respectively) were
associated with a reduction of breast densities (OR, 0.28; 95% confidence interval, 0.15–0.54) compared with those consuming
<100 IU/d and <750 mg/d. Increases in vitamin D and calcium intakes were associated with decreases in breast densities, suggesting
that dietary vitamin D and calcium could reduce breast cancer risk possibly through influences on breast tissue morphology.
Background: Dietary vitamin D has been associated with lower mammographic breast density, a strong biomarker for breast cancer
risk. Blood 25-hydroxyvitamin D 25(OH)D is an integrated measure of ...vitamin D status (from food, supplements, and sun exposure)
and varies with season. Our objective was to assess seasonal variations of breast density and compare such variations, if
any, with that of 25(OH)D.
Methods: This cross-sectional study includes 741 premenopausal women recruited at screening mammography. Plasma 25(OH)D at
recruitment was measured by RIA. Breast density was evaluated using a computer-assisted method. Seasonal variations were modeled
using multivariate linear regression and semi-parametric cubic smoothing splines.
Results: Season was strongly associated with 25(OH)D ( P < 0.0001). The highest smoothed mean 25(OH)D levels were seen at the end of July (81.5 nmol/L) and the lowest in mid-April
(52.4 nmol/L). Breast density showed modest seasonal variations ( P = 0.028). The lowest smoothed mean breast density was observed in early December (38.5%) and the highest at the beginning
of April (44.3%). When a 4-month lag time was presumed, seasonal variations of breast density appeared to be a mirror image
of those of 25(OH)D, and the correlation of daily smoothed estimates of mean breast density and 25(OH)D was negative and strong
( r = −0.90).
Conclusion: In premenopausal women, changes in blood vitamin D seem to be inversely related to changes in breast density with
a lag time of about 4 months. This finding encourages further investigation of the possibility that vitamin D could reduce
breast density and breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(5):929–33)
Background: A better understanding of factors that affect breast density, one of the strongest breast cancer risk indicators,
may provide important clues about breast cancer etiology and prevention. ...This study evaluates the association of vitamin D
and calcium, from food and/or supplements, to breast density in premenopausal and postmenopausal women separately.
Methods: A total of 777 premenopausal and 783 post-menopausal women recruited at two radiology clinics in Quebec City, Canada,
in 2001 to 2002, completed a food frequency questionnaire to assess vitamin D and calcium. Breast density from screening mammograms
was assessed using a computer-assisted method. Associations between vitamin D or calcium and breast density were evaluated
using linear regression models. Adjusted means in breast density were assessed according to the combined daily intakes of
the two nutrients using generalized linear models.
Results: In premenopausal women, total intakes of vitamin D and calcium were inversely related to breast density ( β = −1.4; P = 0.004 for vitamin D; β = −0.8; P = 0.0004 for calcium). In multivariate linear regression, simultaneous increments in daily total intakes of 400 IU vitamin
D and 1,000 mg calcium were associated with an 8.5% (95% confidence interval, 1.8-15.1) lower mean breast density. The negative
association between dietary vitamin D intake and breast density tended to be stronger at higher levels of calcium intake and
vice versa. Among postmenopausal women, intakes of vitamin D and calcium were not associated with breast density.
Conclusion: These findings show that higher intakes of vitamin D and calcium from food and supplements are related to lower
levels of breast density among premenopausal women. They suggest that increasing intakes of vitamin D and calcium may represent
a safe and inexpensive strategy for breast cancer prevention.
Vitamin D has been associated with reduced breast cancer risk. We studied the association of two vitamin D receptor (VDR) gene single nucleotide polymorphisms restriction enzyme detecting SNP of VDR ...(FokI and BsmI) with breast cancer risk in two independent case–control studies carried out in the same population. The modifying effect of family history of breast cancer on this relationship was also evaluated. The first and second studies included respectively 718 (255 cases/463 controls) and 1596 (622 cases/974 controls) women recruited in Quebec City, Canada. FokI and BsmI genotypes were assessed. Relative risks of breast cancer were estimated by multivariate logistic regression. Compared with homozygotes for the common F allele (FF genotype), FokI ff homozygotes had a higher breast cancer risk (study 1: odds ratio (OR)=1.22, 95% confidence interval (CI)=0.76–1.95; study 2: OR=1.44, 95% CI=1.05–1.99; and combined studies: OR=1.33, 95% CI=1.03–1.73). Significant interactions were observed between FokI and family history of breast cancer in the two studies as well as in the combined analysis (P interaction=0.031, 0.050 and 0.0059 respectively). Among women without family history, odds ratios were 1.00, 1.27 (95% CI=1.02–1.58) and 1.57 (95% CI=1.18–2.10) respectively for FF, Ff and ff carriers (Ptrend=0.0013). BsmI Bb+bb genotypes were associated with a weak non-significant increased risk in the two studies (combined OR=1.22, 95% CI=0.95–1.57) without interaction with family history. Results support the idea that vitamin D, through its signalling pathway, can affect breast cancer risk. They also suggest that variability in observed associations between VDR FokI and breast cancer from different studies may partly be explained by the proportion of study subjects with a family history of breast cancer.
BACKGROUND: The effect of multivitamin-multimineral supplements on the occurrence of chronic diseases, such as breast cancer, is unclear. Breast density is increasingly used as a biomarker of breast ...cancer risk. OBJECTIVE: The present study evaluated the association of multivitamin-multimineral supplement use with breast density. DESIGN: Premenopausal (n = 777) and postmenopausal (n = 783) women were recruited at the time of screening mammography. Anthropometric measurements were taken at recruitment. Demographic characteristics, behavioral factors, and health conditions were documented by telephone interview. Diet and multivitamin-multimineral and individual vitamin and mineral supplement use were assessed with a self-administered food-frequency questionnaire. Breast density from screening mammograms was measured using a computer-assisted method. Crude and adjusted means in breast density were evaluated according to multivitamin-multimineral supplement use using generalized linear models. RESULTS: Current multivitamin-multimineral supplement use was reported by 21.7% of women (20.7% and 22.6% of premenopausal and postmenopausal women, respectively). Premenopausal women who were currently using multivitamin-multimineral supplements had higher adjusted mean breast density (45.5%) than past (42.9%) or never (40.2%) users (P for heterogeneity = 0.03, P for trend = 0.009). Of the current users, breast density was not related to duration of multivitamin-multimineral supplement use. In postmenopausal women, multivitamin-multimineral supplement use was not associated with breast density (P for heterogeneity = 0.53, P for trend = 0.40). CONCLUSION: Regular use of multivitamin-multimineral supplements may be associated with higher mean breast density among premenopausal women. The relations of multivitamin-multimineral supplement use to breast density and breast cancer risk need to be clarified.
In women with breast cancer who smoke, it is unclear whether smoking could impair their survival from the disease.
We examined the relation of smoking at diagnosis to breast cancer-specific and ...overall survival among 5,892 women with invasive breast cancer treated in one Canadian center (1987 to 2008). Women were classified as never, former or current smokers. Current smokers were further classified according to total, intensity and duration of smoking. Deaths were identified through linkage to population mortality data. Cox proportional-hazards multivariate models were used. A systematic review with meta-analysis combines new findings with published results.
Compared with never smokers, current smokers at diagnosis had a slightly, but not statistically significant, higher breast cancer-specific mortality (hazard ratio = 1.15, 95% confidence interval (CI): 0.97 to 1.37). Among current smokers, breast cancer-specific mortality increased with total exposure to, intensity and duration of smoking (all Ptrend <0.05). Compared to never smokers, breast cancer-specific mortality was 32 to 56% higher among heavy smokers (more than 30 pack years of smoking, more than 20 cigarettes per day or more than 30 years of smoking). Smoking at diagnosis was associated with an increased all-cause mortality rate. A meta-analysis of all studies showed a statistically significant, 33% increased mortality from breast cancer in women with breast cancer who are smokers at diagnosis compared to never smokers (hazard ratio = 1.33, 95% CI: 1.12 to 1.58).
Available evidence to date indicates that smoking at diagnosis is associated with a reduction of both overall and breast cancer-specific survival. Studies of the effect of smoking cessation after diagnosis on breast cancer-specific outcomes are needed.
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