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. Author manuscript; available in PMC: 2013 Apr 1.
Published in final edited form as: Breast Cancer Res Treat. 2011 Dec 1;132(2):683–691. doi: 10.1007/s10549-011-1885-4

Vitamin D intake, vitamin D receptor polymorphisms, and breast cancer risk among women living in the southwestern U.S.

Dana E Rollison 1,✉, Ashley L Cole 2, Ko-Hui Tung 3, Martha L Slattery 4, Kathy B Baumgartner 5, Tim Byers 6, Roger K Wolff 7, Anna R Giuliano 8
PMCID: PMC3390020  NIHMSID: NIHMS377441  PMID: 22130867

Abstract

No studies of dietary vitamin D intake and vitamin D receptor (VDR) have been conducted comparing breast risk among Hispanic women and non-Hispanic white (NHW) women. We investigated the association between vitamin D intake and breast cancer in a population-based case–control study of 1,527 NHW and 791 Hispanic breast cancer cases diagnosed in 1999–2004 in Arizona, New Mexico, Utah, and Colorado, and 1,599 NHW and 922 Hispanic age-matched controls. Vitamin D intake was assessed using food frequency questionnaires, and associations with breast cancer were adjusted for age, ethnicity, state, education, body mass index, smoking, age at menarche, age at first birth, parity, hormone exposure, height, and physical activity using logistic regression. BsmI, Poly A and FokI vitamin D receptor (VDR) genotypes were also measured. Dietary vitamin D intake was positively associated with breast cancer (highest vs. lowest quartile (Q4 vs. Q1): odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15–1.60; Ptrend = 0.003), whereas vitamin D supplement use was inversely associated with breast cancer (10+ µg/day vs. none: OR = 0.79, 95% CI = 0.65–0.96, Ptrend = 0.01). Similar patterns in risk were observed by ethnicity and menopausal status. Positive associations with dietary vitamin D intake and inverse associations with supplement use were observed for ER+/PR+ and ER−/PR− breast cancers, but not for ER+/PR−disease. BsmI genotype significantly modified the association between dietary vitamin D and breast cancer overall. Future research is needed to better understand potential differences in breast cancer risk by vitamin D source and hormone receptor status.

Keywords: Breast cancer, Vitamin D, Vitamin D receptor, Hispanics, Diet

Introduction

Higher levels of circulating vitamin D metabolites have been consistently associated with decreased risk of breast cancer in several epidemiologic studies [1–5]. In contrast, epidemiologic studies of dietary vitamin D intake and breast cancer have been mostly null [6–13], perhaps due in part to the relatively minor contribution of dietary intake to circulating 25-hydroxyvitamin D [25(OH)D] level. However, most of the women in the previous studies were white, and the relative contribution of diet and sunlight exposure to circulating vitamin D metabolites may differ by ethnicity.

For example, some subgroups of Hispanic women in the U.S. are more likely to eat native Mexican foods than non-Hispanic white (NHW) women, including Mexican cheeses and other foods containing vitamin D [14]. Conversely, Hispanic women on average have darker constitutive skin pigmentation, which may reduce their biologically effective dose of UV radiation, in turn resulting on reduced vitamin D synthesis from sun exposure [15, 16]. Therefore, the impact of dietary vitamin D intake on circulating levels of [25(OH)D] may be higher among Hispanic than NHW women [14]. Furthermore, these ethnic differences in dietary vitamin D intake may partially explain the reduced incidence of breast cancer among Hispanic women compared with NHW women in the U.S. However, no previous studies of dietary vitamin D intake and breast cancer have been conducted among Hispanic women.

To investigate the association between dietary intake of vitamin D and breast cancer among Hispanic and non-Hispanic white women, we conducted a population-based case–control study among women living in the U.S. Southwest using a standardized food frequency questionnaire modified to include foods typically consumed in the Mexican diet. Genotyping of the vitamin D receptor (VDR) gene also was conducted to examine ethnic differences in VDR-associated breast cancer risk.

Materials and methods

Study population

The study design and methods of the 4-Corners Breast Cancer Study have been previously described in detail [17, 18]. Briefly, a population-based case–control study of breast cancer was conducted to investigate differences in the breast cancer risk profiles of Hispanic and non-Hispanic women living in Colorado, New Mexico, Utah and selected counties of Arizona. Sampling was stratified by race/ethnicity, and women who self-reported their race as NHW, Hispanic, or American Indian not living on reservations were eligible. Histologically confirmed first primary breast cancer cases (in situ or invasive) were identified between October 1999 and May 2004 (ICDO sites C50.0–C50.6 and C50.8–C50.9) through population-based cancer registries in each state. Information on estrogen receptor (ER) and progesterone receptor (PR) status of tumors was available through the cancer registries for approximately 70 percent of cases.

Population-based controls were frequency-matched to cases in 5-year age groups. Control participants under 65 were randomly selected from driver’s license lists in New Mexico and Utah, and from commercial mailing lists in Colorado and Arizona. In all states, women 65 years and older were randomly selected from the Center for Medicare Services (Social Security lists). Of all women contacted, 2,325 cases (68%) and 2,525 (42%) controls participated in the study [18], with participants and nonparticipants having similar community socioeconomic characteristics [19]. Ages ranged from 24 to 79 years, and 65% of women were postmenopausal. All participants signed informed written consent. The study protocol was approved by the Institutional Review Board at each institution.

Data collection

A computerized questionnaire was administered in-person by trained and certified interviewers to obtain information on medical and reproductive histories, lifestyle factors, and family history of cancer. Study participants were given the option of having the interview administered in either English or Spanish. For several questions, women were asked to provide information for a reference period defined as 1 year prior to diagnosis for the cases or selection for the controls. Dietary intake information during the referent period was obtained through a questionnaire modeled after the Coronary Artery Risk Development in Young Adults (CARDIA) study and adapted to include ethnic and other foods commonly consumed in the study region [20, 21]. Major dietary sources of vitamin D included fatty fish, eggs, milk, yogurt, and cheese. Dietary history included specific foods consumed, the frequency of consumption (times per day, week, year), as well as portion sizes. Vitamin intake was also assessed, including the type of vitamin/mineral taken, frequency of intake and dose. Daily vitamin D (µg/day) was calculated from the questionnaire using the Nutritional Data System for Research (NDS-R) Database Version, 4.02_30 (©Regents of the University of Minnesota). Information on vitamin D intake was available for 2,318 cases and 2,521 controls. One woman who reported a dietary vitamin D intake of 3,886 µg per day was excluded from the analysis of vitamin D intake.

Blood samples for genotyping were available for 1,740 (75.1%) cases and 2,051 (81.4%) controls. Three VDR genotypes, including two single nucleotide polymorphisms (BsmI, FokI) and a polyadenosine (Poly A) repeat variant were assessed using PCR and restriction fragment length polymorphism (RFLP) methods with modifications [22–24]. As is the convention, a lower case letter was used to denote the presence of the restriction or start site (“b” for BsmI [rs 154410] and “f” for FokI [2228570 (previously known as rs10735810)]), while an upper case letter was used to denote the absence of the restriction or start site (“B” and “F” for BsmI and FokI, respectively). The length of Poly A variants were designated as long (L) (18–22 repeats) or short (S) (14–17 repeats).

Statistical methods

Quartiles of dietary vitamin D intake were defined based on the distributions in controls. Quartile ranges are presented in both micrograms (µg) and international units (IU) in Table 1. A clear bimodal distribution of vitamin D supplementation was observed in the controls, resulting in a natural cutoff of <10 versus 10+ µg/day among users. Associations between vitamin D intake, VDR, and breast cancer were estimated by calculating odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression, adjusting for age, ethnicity, study center, education, body mass index (BMI (<25, 25–29.9, and 30+ kg/m2), smoking, age at menarche, age at first birth, parity, height, lifetime physical activity, and recent hormone exposure. (Recent hormone exposure was defined as “positive” for women who reported having taken hormone replacement therapy (HRT) in the past 2 years; and “negative” for postmenopausal women who did not take HRT within the past 2 years.) Main effects of vitamin D intake were also adjusted for total calorie intake, total dietary fat and total calcium intake, and no appreciable differences in ORs were observed. Therefore, subsequent analyses did not include adjustment for these factors. Trends between vitamin D intake and breast cancer were assessed using a variable set to equal the median value of the respective category of vitamin D intake for each woman.

Table 1.

Dietary vitamin D intake, supplement use, vitamin D receptor genotype, and breast cancer among women living in the U.S. Southwest, 1999–2004

Cases (n = 2,318) Controls (n = 2,521) Age-adjusted Full modela
n % n % OR 95% CI OR 95% CI
Vitamin D intake (cases n = 2,317)
  Dietary intakeb
    Quartile 1 483 20.8 630 25.0 1.00 Reference 1.00 Reference
    Quartile 2 614 26.5 631 25.0 1.26 1.07–1.49 1.28 1.08–1.51
    Quartile 3 586 25.3 629 25.0 1.20 1.02–1.41 1.23 1.04–1.45
    Quartile 4 634 27.4 631 25.0 1.28 1.09–1.50 1.35 1.15–1.60
Ptrend = 0.02 Ptrend = 0.003
  Supplements
    None 951 41.0 959 38.0 1.00 Reference 1.00 Reference
    <10 µg (<400 IU) 1,134 49.0 1,261 50.0 0.93 0.83–1.05 0.90 0.79–1.02
    10+ µg (400+ IU) 232 10.0 301 11.9 0.82 0.67–1.00 0.79 0.65–0.96
Ptrend = 0.05 Ptrend = 0.01
Vitamin D receptor (VDR)
  BsmI genotype
    GG (bb) 684 39.3 864 42.2 1.00 Reference 1.00 Reference
    GA (Bb) 809 46.5 905 44.2 1.14 0.99–1.30 1.12 0.97–1.29
    AA (BB) 247 14.2 278 13.6 1.13 0.93–1.38 1.10 0.90–1.34
  Poly A genotypec
    LL 699 40.7 888 43.6 1.00 Reference 1.00 Reference
    LS 773 45.1 875 43.0 1.13 0.98–1.30 1.11 0.96–1.28
    SS 244 14.2 274 13.5 1.14 0.94–1.39 1.11 0.90–1.36
  FokI genotype
    CC (FF) 662 38.1 752 36.7 1.00 Reference 1.00 Reference
    CT (Ff) 807 46.5 983 47.9 0.93 0.81–1.07 0.94 0.82–1.08
    TT (ff) 268 15.4 316 15.4 0.96 0.79–1.16 0.99 0.81–1.20
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a

Adjusted for age, ethnicity, study center, education, body mass index, smoking, age at menarche, age at first birth, parity, recent hormone exposure, height, and lifetime physical activity

b

Quartiles (Q) 1–4 of dietary vitamin D intake corresponded to the following ranges expressed in micrograms (Q1: 0.174–3.063, Q2: 3.064–5.065, Q3: 5.066–7.712; Q4: 7.713–34.067) and international units (IU) (Q1: 7.0–122.5; Q2: 122.6–202.6; Q3: 202.7–308.5; Q4: 308.6–1362.7)

c

L long; S short

Departures from Hardy–Weinberg equilibrium were assessed for VDR genotypes among controls using the Chisquare test. Associations between VDR genotypes and breast cancer were modeled for each individual genotype, using women who were homozygous for the more common allele as the reference category (GG (bb) for BsmI, CC (FF) for FokI, and LL (long/long) for Poly A. Main effects for vitamin D intake, VDR genotypes and breast cancer were stratified by ethnicity (NHW and Hispanics) and menopausal status (pre/perimenopausal and postmenopausal). Interactions between VDR genotypes and vitamin D intake in relation to breast cancer were assessed through simultaneous stratification of results by both factors, and statistical significance of the interactions were determined using the Wald test for the interaction terms in the logistic regression models. Associations between vitamin D intake and breast cancer were also investigated by hormone receptor status of the tumors (ER+/PR+, ER+/PR−, and ER−/PR−). (There were too few numbers of ER−/PR+ cases for a separate group.) All tests used a significance level of P ≤ 0.05. All data were analyzed using SAS version 9.1 (SAS Institute, Cary, NC).

Results

Among controls, dietary vitamin D intake ranged from 0.174 to 34.1 µg/day (7–1,363 IU) (Table 1). A statistically significant age-adjusted positive association was observed between higher dietary vitamin D intake and breast cancer (odds ratio (OR) for the highest quartile (Q4) versus lowest quartile (Q1) = 1.28, 95% CI = 1.09–1.50, P for trend = 0.02). A similar association was observed after adjustment for age, race, study center, BMI, smoking, age atmenarche, age at first birth, parity, recent hormone exposure, height, and lifetime physical activity (OR = 1.35, 95% CI = 1.15–1.60; P for trend = 0.003). Additional adjustment for total calorie intake, total fat intake and total calcium intake did not appreciably change the risk estimates (Q4 vs. Q1: OR = 1.43, 95% CI = 1.15–1.79, P for trend = 0.008). Vitamin D supplementation was inversely associated with breast cancer, with a statistically significant decreased risk of breast cancer observed for 10+ µg of vitamin D supplement intake per day (OR = 0.79, 95% CI = 0.65–0.96; P for trend = 0.01). Similar associations were observed when analyses were restricted to the 83% of breast cancer cases that were invasive (data not shown).

Positive associations between dietary vitamin Dintake and breast cancer risk were observed in both NHW women and Hispanic women (P for trend = 0.04 for both groups), with statistically significant increased risks observed for Q4 vs. Q1 (OR = 1.29, 95% CI = 1.05–1.60 in NHW; OR = 1.46, 95% CI = 1.10–1.94 in Hispanics) (Table 2). Vitamin D supplementation was not clearly associated with breast cancer among NHW women, while a statistically significant decreased risk of breast cancer was observed for 10+ µg/day among Hispanic women (OR = 0.68, 95%CI = 0.47–0.97). However, the interaction between vitamin D supplement use, ethnicity, and breast cancer was not statistically significant (P = 0.62). None of the VDR genes were associated with breast cancer among NHW or Hispanic women. No departures from Hardy–Weinberg equilibrium were observed among controls for the single nucleotide polymorphisms.

Table 2.

Vitamin D intake, VDR genotypes and breast cancer among non-Hispanic White and Hispanic women

Non-Hispanic White women Hispanic women P for interaction
Cases Controls ORa 95% CIa Cases Controls ORa 95% CIa
n % n % n % n %
Vitamin D intake
  Dietary intake
    Quartile 1 314 20.6 383 24.0 1.00 Reference 169 21.4 247 26.8 1.00 Reference
    Quartile 2 401 26.3 402 25.1 1.22 1.00–1.50 213 26.9 229 24.8 1.41 1.07–1.87
    Quartile 3 396 25.9 411 25.7 1.21 0.98–1.49 190 24.0 218 23.6 1.26 0.94–1.67
    Quartile 4 415 27.2 403 25.2 1.29 1.05–1.59 219 27.7 228 24.7 1.46 1.10–1.94 0.57
Ptrend = 0.04 Ptrend = 0.04
  Supplements
    None 539 35.3 507 31.7 1.00 Reference 412 52.1 452 49.0 1.00 Reference
    <10 mcg 814 53.4 888 55.5 0.86 0.74–1.01 320 40.5 373 40.5 0.96 0.78–1.19
    10+ mcg 173 11.3 204 12.8 0.82 0.64–1.05 59 7.5 97 10.5 0.68 0.47–0.97 0.62
Ptrend = 0.05 Ptrend = 0.09
VDR
  BsmI genotype
    GG (bb) 399 34.1 478 36.0 1.00 Reference 285 49.9 386 53.7 1.00 Reference
    GA (Bb) 579 49.5 631 47.5 1.11 0.93–1.33 230 40.3 274 38.1 1.13 0.89–1.43
    AA (BB) 191 16.3 219 16.5 1.05 0.83–1.33 56 9.8 59 8.2 1.24 0.83–1.86 0.33
  Poly A genotypeb
    LL 411 35.7 491 37.3 1.00 Reference 288 51.1 397 55.2 1.00 Reference
    LS 548 47.6 616 46.7 1.08 0.90–1.29 225 39.9 259 36.0 1.19 0.94–1.51
    SS 193 16.8 211 16.0 1.09 0.86–1.39 51 9.0 63 8.8 1.11 0.74–1.67 0.50
  FokI genotype
    CC (FF) 461 39.6 508 38.3 1.00 Reference 201 35.1 244 33.7 1.00 Reference
    CT (Ff) 533 45.8 631 47.6 0.93 0.79–1.11 274 47.9 352 48.6 0.93 0.72–1.20
    TT (ff) 171 14.7 188 14.2 1.04 0.81–1.33 97 17.0 128 17.7 0.91 0.66–1.27 0.64
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a

Adjusted for age, study center, education, body mass index, smoking, age at menarche, age at first birth, parity, recent hormone exposure, height, and lifetime physical activity

b

L long; S short

Associations between vitamin D intake and breast cancer did not vary by menopausal status (data not shown). Higher levels of dietary vitamin D intake were associated with increased risks of both premenopausal breast cancer (Q4 vs. Q1: OR = 1.37, 95% CI = 1.03–1.83) and postmenopausal breast cancer (Q4 vs. Q1: OR = 1.37, 95% CI = 1.12–1.68), with a statistically significant trend observed only for postmenopausal women (P = 0.005), most likely due to the larger sample size. Vitamin D supplementation of 10+ µg/day was associated inversely with both pre- and postmenopausal breast cancer, although none of the individual ORs were statistically significant. No statistically significant associations of either pre- or postmenopausal breast cancer were observed with the VDR genotypes.

Higher dietary vitamin D intake was statistically significantly associated with increased breast cancer risk among women with at least one BsmI A allele (Bb + BB) VDR genotype (Q4 vs. Q1: OR= 1.48, 95% CI = 1.16–1.89; P for trend = 0.006), while no associations were observed among those women with the GG (bb) genotype (P for interaction = 0.04) (Table 3). A similar pattern was observed for the Poly A VDR genotype, with increased risks of breast cancer associated with higher dietary vitamin D intake among women with long/short (LS) or short/short (SS) Poly A genotypes (Q4 vs. Q1: OR = 1.41, 95% CI = 1.10–1.81; P for trend = 0.02) but not among those with the long/long (LL) Poly A genotype (P for interaction = 0.09). Dietary vitamin D intake also was positively associated with breast cancer among women with the FokI CC (FF) genotype (Q4 vs. Q1: OR = 1.43, 95% CI = 1.04–1.96; P for trend = 0.05), whereas no pattern of association was observed among women with CT and TT (Ff and ff) FokI genotypes (P for interaction = 0.07). In contrast to the interactions observed for dietary vitamin D intake, none of the three VDR genotypes significantly modified the inverse associations observed between vitamin D supplementation and breast cancer risk. When the interactions between vitamin D and VDR genotypes were examined by ethnicity, there were no substantive differences between NHW and Hispanic women (data not shown).

Table 3.

Dietary vitamin D, supplement use and breast cancer by VDR genotypes

Vitamin D intake Cases Controls ORa 95% CIa Cases Controls ORa 95% CIa P for interaction
n % n % n % n %
BsmI genotype (rs1544410): GG (bb) GA + AA (Bb + BB)
  Dietary intake
    Quartile 1 148 21.6 197 22.8 1.00 Reference 224 21.2 301 25.4 1.00 Reference
    Quartile 2 182 26.6 211 24.4 1.13 0.84–1.53 286 27.1 303 25.6 1.29 1.02–1.64
    Quartile 3 177 25.9 220 25.5 1.06 0.78–1.42 247 23.4 299 25.3 1.14 0.89–1.46
    Quartile 4 177 25.9 236 27.3 1.01 0.75–1.36 298 28.3 280 23.7 1.48 1.16–1.89
Ptrend = 0.77 Ptrend = 0.006 Pint = 0.04
  Supplements
    None 299 43.7 324 37.5 1.00 Reference 401 38.0 429 36.3 1.00 Reference
    <10 mcg 314 45.9 445 51.5 0.79 0.63–1.99 547 51.9 614 51.9 0.94 0.78–1.14
    10+ mcg 71 10.4 95 11.0 0.87 0.61–1.25 107 10.1 140 11.8 0.80 0.59–1.07
Ptrend = 0.14 Ptrend = 0.16 Pint = 0.41
Poly A genotype: LL (long/long) LS (long/short) + SS (short/short)
  Dietary intake
    Quartile 1 144 20.6 203 22.9 1.00 Reference 221 21.7 289 25.2 1.00 Reference
    Quartile 2 195 27.9 219 24.7 1.24 0.92–1.66 272 26.8 296 25.8 1.22 0.96–1.56
    Quartile 3 179 25.6 226 25.5 1.10 0.81–1.48 239 23.5 290 25.2 1.11 0.86–1.42
    Quartile 4 181 25.9 240 27.0 1.06 0.79–1.43 284 28.0 274 23.9 1.41 1.10–1.81
Ptrend = 0.89 Ptrend = 0.02 Pint = 0.09
  Supplements
    None 302 43.2 334 37.6 1.00 Reference 389 38.3 417 36.3 1.00 Reference
    <10 mcg 325 46.5 458 51.6 0.81 0.65–1.01 524 51.6 594 51.7 0.94 0.78–1.14
    10+ mcg 72 10.3 96 10.8 0.91 0.64–1.30 103 10.1 138 12.0 0.79 0.58–1.07
Ptrend = 0.22 Ptrend = 0.15 Pint = 0.59
FokI genotype (rs2228570): CC (FF) CT + TT (Ff + ff)
  Dietary intake
    Quartile 1 127 19.2 178 23.7 1.00 Reference 242 22.5 321 24.7 1.00 Reference
    Quartile 2 188 28.4 207 27.5 1.28 0.94–1.74 281 26.2 309 23.8 1.22 0.96–1.54
    Quartile 3 170 25.7 187 24.9 1.31 0.96–1.80 255 23.7 332 25.6 1.01 0.80–1.29
    Quartile 4 177 26.7 180 23.9 1.43 1.04–1.96 296 27.6 337 25.9 1.22 0.96–1.54
Ptrend = 0.05 Ptrend = 0.25 Pint = 0.07
  Supplements
    None 253 38.2 255 33.9 1.00 Reference 445 41.4 501 38.6 1.00 Reference
    <10 mcg 342 51.7 416 55.3 0.80 0.63–1.02 518 48.2 643 49.5 0.91 0.76–1.09
    10+ mcg 67 10.1 81 10.8 0.80 0.54–1.18 111 10.4 155 11.9 0.83 0.62–1.10
Ptrend = 0.10 Ptrend = 0.16 Pint = 0.73
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a

Adjusted for age, ethnicity, study center, education, body mass index, smoking, age at menarche, age at first birth, parity, recent hormone exposure, height, and lifetime physical activity

Higher dietary vitamin D intake was significantly associated with breast cancers of ER+/PR+ (Q4 vs. Q1: OR = 1.35, 95% CI = 1.08–1.68, P for trend = 0.05) and ER−/PR− (Q4 vs. Q1: OR = 1.63, 95% CI = 1.14–2.34, P for trend = 0.01), but not with ER+/PR− cancer (Table 4). Similarly, statistically significant inverse associations were observed between vitamin D supplementation and ER+/PR+ breast cancer (10+ vs. 0 µg: OR = 0.74, 95% CI = 0.57–0.96, P for trend = 0.008) and ER−/PR− disease (10+ vs. 0 µg: OR = 0.44, 95% CI = 0.26–0.75, P for trend = 0.002), but not for ER+/PR− cancers (10+ vs. 0 µg: OR = 0.98, 95% CI = 0.57–1.70, P for trend = 0.70).

Table 4.

Dietary vitamin D, supplement use and breast cancer by ER/PR status

Vitamin D intake Controls ER+/PR+ cases ER+/PR− cases ER−/PR− cases
n % n % ORa 95% CIa n % ORa 95% CIa n % ORa 95% CIa
Dietary intake
  Quartile 1 630 25.0 206 20.7 1.00 Reference 52 29.6 1.00 Reference 54 18.0 1.00 Reference
  Quartile 2 631 25.0 277 27.8 1.34 1.08–1.66 35 19.9 0.67 0.43–1.04 74 24.7 1.35 0.93–1.96
  Quartile 3 629 25.0 239 24.0 1.17 0.94–1.46 42 23.9 0.84 0.55–1.28 77 25.7 1.38 0.95–2.00
  Quartile 4 631 25.0 274 27.5 1.35 1.08–1.68 47 26.7 0.92 0.61–1.40 95 31.7 1.63 1.14–2.34
Ptrend = 0.05 Ptrend = 0.91 Ptrend = 0.01
Supplements
  None 959 38.0 420 42.2 1.00 Reference 61 34.7 1.00 Reference 145 48.3 1.00 Reference
  <10 mcg 1,261 50.0 478 48.0 0.84 0.71–0.99 96 54.6 1.21 0.85–1.70 138 46.0 0.80 0.61–1.03
  10+ mcg 301 11.9 98 9.8 0.74 0.57–0.96 19 10.8 0.98 0.57–1.70 17 5.7 0.44 0.26–0.75
Ptrend = 0.008 Ptrend = 0.70 Ptrend = 0.002
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a

Adjusted for age, ethnicity, study center, education, body mass index, smoking, age at menarche, age at first birth, parity, recent hormone exposure, height, and lifetime physical activity

Discussion

Overall, dietary vitamin D was positively associated with breast cancer, while vitamin D supplement was inversely associated with breast cancer. The positive associations with dietary vitamin D intake were observed for both pre-and postmenopausal breast cancer, and among both NHW and Hispanic women. Our findings of a positive association between dietary vitamin D intake and breast cancer are inconsistent with previous epidemiologic studies of mostly white women, which observed either an inverse association [13, 25, 26] or no association [6–13]. Previous studies of vitamin D supplementation and breast cancer also have been mostly null [8, 10, 12]. Similar to our findings, a recent case–control study reported a significant inverse relationship of vitamin D supplement intake >10 µg/day with premenopausal breast cancer risk [27].

Several possible explanations exist for the positive association observed between dietary vitamin D intake and breast cancer in the current study, the first of which is chance. Although all analyses were adjusted for conventional breast cancer risk factors, and additional adjustment for dietary fats, calcium and total calories did not attenuate the observed positive associations, there may have been residual confounding. For example, women who consume higher levels of dietary vitamin D may be more likely to consume foods comprising a “Western diet” pattern, which has been shown to be associated with increased breast cancer risk [14]. However, adjustment for dietary patterns did not diminish the observed positive association between dietary vitamin D and breast cancer (data not shown). Furthermore, no specific source of dietary vitamin D was associated with breast cancer more than any other, based on analyses of specific foods (milk, cheeses, yogurts, etc.). We also considered possible effect modification of the association between dietary vitamin D and breast cancer by several factors including body mass index, total calories, total fat intake, and total calcium intake, and observed no statistically significant differences between groups. However, residual confounding and/or effect modification by unmeasured factors cannot be ruled out. Furthermore, although study participants did not differ from non-participants with respect to socioeconomic factors [19], no information on vitamin D intake, supplement use, or other potential confounding factors was available for non-participants. If participants differed from non-participants with respect to these factors, it is possible the observed results could have been biased.

The contrast between the positive associations of dietary vitamin D intake and the inverse associations of vitamin D supplementation with breast cancer may be due to differences in misclassification of exposures. Dietary vitamin D intake is based on dietary recall of the consumption of specific foods, coupled with estimation of the vitamin D content of those foods using a validated database. There may be measurement errors in both steps. Although vitamin D supplementation also was based on self-report, one’s ability to recall supplement use may be more precise than the ability to recall consumption of specific foods, both with respect to frequency of intake and amount or dose. However, if the magnitude of exposure misclassification was similar among breast cancer cases and controls, then the observed positive association between dietary vitamin D intake and breast cancer would represent an underestimation.

Lower circulating vitamin D [25(OH)D] levels have been previously associated with increased breast cancer mortality [28]. To investigate the effect of survival time after cancer diagnosis on study results, we stratified the associations between dietary and supplement intake of vitamin D and breast cancer by the length of time between breast cancer diagnosis and study interview. The positive association between high levels of dietary vitamin D intake and breast cancer was consistently observed across women interviewed less than 1 year, 1–2 years or more than 2 years after diagnosis, suggesting survival time did not bias the dietary vitamin D results. Regarding supplement use, those cases who were interviewed more than 2 years after diagnosis were less likely to report having taken 10+ µg of vitamin D per day during the reference period (one year prior to diagnosis) as compared with those who were interviewed within one year of diagnosis (P = 0.01). Although this observation is not consistent with the reported association between vitamin D intake and breast cancer survival, it is possible that cases in the current study were less likely to recall their supplement use the further out the interview was from the reference period.

Although there were no statistically significant differences in the inverse associations observed between vitamin D supplement use and breast cancer among NHW versus Hispanic women, the inverse association for 10+ µg/day was greater in magnitude and statistically significant among Hispanic women despite the substantially smaller sample size. There may be ethnic differences in the relative contribution of oral vitamin D intake versus vitamin D synthesis from sunlight exposure to circulating vitamin D levels. Dietary vitamin D intake is thought to be a minor source of circulating 25(OH)D concentrations, as compared with vitamin D derived from sun exposure [29]. However, some [15, 16] but not all [30, 31] studies suggest that increased skin pigmentation reduces the dose of UV exposure, resulting in less vitamin D synthesis. Thus, if Hispanic women in the current study experienced lower circulating vitamin D levels compared with white women under the same amount of sun exposure, then vitamin D supplementation would have had a greater relative impact on circulating vitamin D levels in Hispanic women.

Both the positive association with dietary vitamin D intake and the inverse association with vitamin D supplementation were of greater magnitude for ER−/PR− breast cancer than for ER+/PR+ breast cancer, despite the smaller sample size of this subgroup. In contrast, neither dietary vitamin D nor supplement use was associated with ER+/PR− breast cancer. Two previous studies have investigated vitamin D in the context of combined ER and PR status, one of which observed inverse associations between vitamin D supplementation in adolescence and ER+/PR+, ER+/PR−, and ER−/PR− breast cancers, with the association reaching statistical significance for only the ER+/PR+ group [32]. Another study observed statistically significant inverse associations between plasma 25(OH)D and breast cancers defined as “ER+ and/or PR+” as well as ER−/PR− cancers [3]. An inverse association between vitamin D supplementation and reduced risk of both ER+ and ER− cancers is consistent with experimental data that Gemini vitamin D analogues have inhibitory effects on both ER+ and ER− mammary tumorigenesis [33]. Overall, emerging evidence suggests that vitamin D supplementation may be potentially important for reducing risk of ER−/PR− breast cancer, a subtype for which few modifiable risk factors have been established.

No statistically significant main effects were observed for BsmI, Poly A, or FokI VDR genotypes among NHW or Hispanic women in the current study. The null findings for both BsmI and Poly A are consistent with the fact that these polymorphisms have been reported to be in linkage disequilibrium [34]. Two recent meta-analyses [35, 36] also observed no association between BsmI genotype and breast cancer. The same two meta-analyses reported a statistically significant but modest increased risk of breast cancer associated with the FokI ff genotype (OR = 1.14 for ff vs. FF [35]), while the another study reported a inverse association [37]. The only VDR results published from Hispanic women are from the multiethnic cohort (MEC) study, in which neither FokI nor BsmI genotypes were associated with statistically significant risk of breast cancer [38], and from a population-based case–control study in which ethnicity-specific risk estimates were not presented [39]. To the best of our knowledge, only two case–control studies have examined the interaction between VDR genotype and dietary vitamin D intake, but neither observed significant interactions between total vitamin D intake and FokI, BsmI or Poly A VDR genotypes in relation to breast cancer [37, 40]. Thus, the statistically significant interaction observed between dietary intake and BsmI genotype in the current study may be due to chance.

This is the first study to investigate the associations between dietary vitamin D, supplementation and breast cancer among Hispanic women. No differences in the directions of these associations were observed between NHW and Hispanic women, although the sample size was too limited to evaluate ethnic differences in the magnitude of these associations and the interactions between dietary vitamin D intake and VDR genotype. Future studies of vitamin D and breast cancer among Hispanic women should include measures of vitamin D dietary intake and supplement use in addition to measures of UV exposure, circulating vitamin D metabolites and hormone receptor status of the tumor to further characterize the role of vitamin D in etiology and, ultimately, the potential for breast cancer prevention.

Acknowledgments

Financial support was provided by the National Institutes of Health (CA078682, CA078762, CA078552, CA078802, CA40002). The Utah Cancer Registry is funded by the National Cancer Institute (Contract # N01-PC-67000) with additional support from the State of Utah Department Health. The New Mexico Tumor Registry and Arizona and Colorado cancer registries are funded by the Centers for Disease Control and Prevention National Program of Cancer Registries.

Contributor Information

Dana E. Rollison, Email: dana.rollison@moffitt.org, Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Ashley L. Cole, Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

Ko-Hui Tung, Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Martha L. Slattery, Health Research Center, University of Utah, Salt Lake City, UT, USA

Kathy B. Baumgartner, Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA

Tim Byers, University of Colorado School of Medicine, Denver, CO, USA.

Roger K. Wolff, Health Research Center, University of Utah, Salt Lake City, UT, USA

Anna R. Giuliano, Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

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