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American Journal of Epidemiology Advance Access originally published online on August 27, 2008
American Journal of Epidemiology 2008 168(8):915-924; doi:10.1093/aje/kwn198
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Vitamin D From Dietary Intake and Sunlight Exposure and the Risk of Hormone-Receptor-Defined Breast Cancer

Kristina M. Blackmore, Maia Lesosky, Heidi Barnett, Janet M. Raboud, Reinhold Vieth and Julia A. Knight

Correspondence to Kristina M. Blackmore, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 60 Murray Street, Box 18, Toronto, Ontario, Canada M5T 3L9 (e-mail: blackmore{at}mshri.on.ca).

Received for publication November 28, 2007. Accepted for publication June 9, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Evidence has emerged for a role of vitamin D in the development of breast cancer, and there is some suggestion that its antiproliferative effect is greater in hormone-receptor-positive cells. Few epidemiologic studies have considered the association between vitamin D and hormone-receptor-defined breast cancer, and the results are conflicting. Considering 759 cases and 1,135 controls from a case-control study (Ontario, Canada, 2003–2005), the authors examined the association between vitamin D intake at specific ages and combined estrogen-receptor- (ER) and progesterone-receptor- (PR) defined breast cancer. While increased intake of vitamin D (from the sun and diet) was most consistently associated with a significantly reduced risk of ER+/PR+ tumors (e.g., odds ratio = 0.76, 95% confidence interval: 0.59, 0.97 for use of cod liver oil during adolescence), comparable nonsignificant associations were found for receptor-negative (ER–/PR–) (odds ratio = 0.74, 95% confidence interval: 0.53, 1.04) and mixed (ER+/PR–) (odds ratio = 0.79, 95% confidence interval: 0.51, 1.22) tumors. This study suggests that vitamin D is associated with a reduced risk of breast cancer regardless of ER/PR status of the tumor. Future studies with a larger number of receptor-negative and mixed tumors are required.

breast neoplasms; case-control studies; diet; receptors, estrogen; receptors, progesterone; sunlight; vitamin D

Abbreviations: ER, estrogen receptor; PR, progesterone receptor; 1,25(OH)2D, 1,25-dihydroxyvitamin D (calcitriol); 25(OH)D, 25-hydroxyvitamin D (calcidiol)


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Studies supporting a role of vitamin D in the prevention of several cancers, including breast cancer, have recently emerged (1–3). Vitamin D is primarily obtained through exposure of the skin surface to ultraviolet B radiation, but small amounts can be ingested through limited dietary sources (e.g., fortified milk, fatty fish) and supplements (4–6). The biologic mechanism by which vitamin D might prevent breast cancer has been summarized previously (5–11). The active form of vitamin D (1,25-dihydroxyvitamin D (1,25(OH)2D)) can inhibit cellular proliferation and induce differentiation and apoptosis in normal and cancerous breast cells (7–10). In carcinogen-exposed rats, 1,25(OH)2D or its analogues have been shown to reduce the incidence and size of tumors and delay mammary tumor development (11). 25(OH)D-1-{alpha} hydroxylase, the enzyme that converts 25-hydroxyvitamin D (25(OH)D) to its active form, and the vitamin D receptor, through which 1,25(OH)2D mediates its effects, are present in normal and cancerous breast epithelia (7–10).

Estrogen receptor (ER) and progesterone receptor (PR) are widely studied markers in breast tissue, and there is evidence that some breast cancer risk factors vary by hormone receptor status (reviewed by Althuis et al. (12)). An antiproliferative effect of 1,25(OH)2D in both ER+ and ER– cell lines has been demonstrated, although some studies suggest the effect is greater in ER+ cells (8, 9). To our knowledge, only 3 studies have examined the association between dietary vitamin D intake and hormone receptor status (13–15), and one considered blood levels of 1,25(OH)2D and hormone receptor status (16). Of these studies, 3 demonstrated a stronger inverse association with risk of receptor-positive tumors (ER+, PR+, ER+/PR+) (13, 14, 16), whereas another demonstrated stronger relative risks for women with a negative ER and PR status (15). Nonetheless, in some studies (13, 15, 16), receptor status was unavailable for a significant proportion of cases (30%–50%); in others, the total number of cases with a negative ER and PR status was very small (n < 100) (14), thereby limiting interpretation of the overall findings. Furthermore, these studies did not assess sun exposure history and hormone receptor status.

In a recently completed, population-based case-control study, we found a strong inverse association between several reported vitamin D exposures from the sun (e.g., odds ratio = 0.65, 95% confidence interval: 050, 0.85 for the highest quartile of outdoor activities vs. the lowest) and diet (e.g., odds ratio = 0.76, 95% confidence interval: 0.62, 0.92 for cod liver oil use) during adolescence and overall breast cancer risk (17). Some evidence was observed for exposures during early adulthood, with little evidence of a relation between perimenopausal exposures and breast cancer (17). To add to the limited literature regarding the relation between vitamin D and hormone-receptor-defined breast cancer, we examined whether the associations observed between reported vitamin D exposures from the sun and diet during these 3 time periods and subsequent breast cancer varied by joint ER and PR status. In contrast to previous studies, receptor status was available for approximately 80% of cases.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Details of the study design and population have previously been described (17). This study was approved by the local institution's research ethics board. We conducted a population-based-case-control study in the province of Ontario, Canada. Cases were identified through the Ontario Cancer Registry and were randomly sampled from women aged less than 70 years with incident, pathology confirmed, first primary invasive breast cancer diagnosed between July 1, 2003, and August 31, 2004. Of the 1,610 eligible cases identified, physician permission to contact 1,350 (84%) was obtained. Of the 1,350 women we attempted to contact, 972 (72%) completed a telephone interview.

For the majority of recruited cases (n = 665, 68%), ER and PR status (positive/negative) was available from pathology reports obtained from the Ontario Cancer Registry. However, for the remaining cases (n = 307, 32%), hormone receptor status was unavailable. For these cases, consent was obtained from 249 women (81%) authorizing release of pathology reports from the medical records departments of hospitals where surgery had been performed. Pathology reports were received for 224 (90%) of these women, 129 (58%) of which contained information on ER and PR status. Immunohistochemical assays were the predominant method used to determine hormone receptor status. In total, ER status was available for 784 cases (81%), PR status was available for 763 cases (78%), and joint ER and PR status (ER+/PR+, ER+/PR–, ER–/PR+, ER–/PR–) was available for 762 cases (78%). A status of "borderline" was considered unknown. Because the number of ER–/PR+ cases was small (n = 3), this category was omitted from the analysis, resulting in a total of 759 cases.

Population controls were women who reported no prior breast cancer and were living in the province of Ontario. Controls were identified through randomly selected residential telephone number lists and were frequency matched to cases by 5-year age group. Of the 1,974 telephone numbers for which an eligible control was identified, 1,376 (70%) potential controls agreed to participate; of these women, 1,135 (82%) completed the telephone interview.

During the interview, cases and controls were asked to recall their sun exposure history and their dietary and supplemental vitamin D intake with respect to 3 age groups: 10–19, 20–29, and 45–54 years (17). These age groups were chosen to capture exposures during breast development in adolescence and early adulthood and breast involution occurring around the time of menopause. Studies have shown that some risk factors (e.g., smoking, ionizing radiation, phytoestrogen intake) may have a greater influence on subsequent breast cancer risk when exposures occur during periods of rapid tissue growth and change (18–20).

Sun-exposure-related variables included number of days per week on which at least half an hour was spent outside (<7 vs. 7), total number of outdoor activity episodes of at least half an hour during the summer (quartiles based on the distribution among controls), ever having a job involving at least half an hour of outdoor work per day (yes/no), usually keeping arms and legs covered when outside in the summer (no, partial coverage, yes), skin usually burned or darkened in the summer (yes/no), usually used sunscreen in the summer (yes/no), ever took a trip to a summer climate in the winter (yes/no), and ever used a sunlamp or sun (tanning) bed (yes/no). In Canada, major food sources of vitamin D are limited, and dietary intake variables included number of glasses of milk per week (none, <5, 5–9, ≥10), number of servings of salmon/tuna (canned or fresh) per week (none, <1, 1, >1), ever took cod liver oil at least once per week (yes/no), and use of vitamin supplements (none, supplements without vitamin D, vitamin D or multivitamins).

Unordered polytomous logistic regression was used to generate odds ratios and their 95% confidence intervals for variables related to vitamin D (from the sun and diet) for each joint hormone receptor subgroup (ER+/PR+, ER+/PR–, ER–/PR–). In this model, the dependent variable (receptor-status-defined breast cancer) was treated as a polytomous nominal variable, and the logit estimator always compared each joint-receptor-status-defined case with the common control group, enabling simultaneous estimation of subgroup-specific risk parameters. Significant differences in odds ratios among the 3 case subgroups for vitamin-D-related exposures were tested by using the Wald statistic P value, which is calculated based on differences in parameter estimates and their covariances from the polytomous logistic regression model (21).

All models included age (continuous), defined as age at diagnosis for cases and age at interview for controls, and all fully adjusted models included education (high school or less, some university or technical school, university graduate) and ethnicity (northern European, mixed or other European, non-European). We considered the following known breast cancer risk factors as potential confounders: age at menarche (≤11, 12, 13, ≥14 years), menopausal status (premenopausal, postmenopausal, unknown), menopausal status with age at menopause (premenopausal, unknown, and age at menopause in 4 categories), hormone therapy ever use (no/yes), age at first birth (<20, 20–24, 25–29, ≥30 years; nulliparous), parity (none, 1, 2, ≥3 births), ever breastfed (no/yes), first-degree family history of breast cancer (no/yes), body mass index (weight (kg)/height (m)2) 2 years prior to the reference date (≤20.0, 20.1–24.9, 25.0–29.9, ≥30), body mass index at age 18 years (≤20.0, 20.1–24.9, ≥25.0), and alcohol use (none, <7 drinks/week, ≥7 drinks/week). In this study, age at menarche, age at first birth, ever breastfed, and first-degree family history were all significantly associated with risk of breast cancer and were therefore also included in the fully adjusted models.

Tests of linear trend were performed by using polytomous logistic regression. Stratified analyses according to menopausal status (premenopausal and postmenopausal) were also executed. Differences in vitamin-D-related exposures between women with known and unknown receptor status were examined by using a chi-square analysis. All analyses were conducted with SAS version 9.1 software (Stata Corporation, College Station, Texas). All tests were 2 sided, with P < 0.05 as the criterion for significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Table 1 describes cases and controls according to demographic and other characteristics. Among the 759 cases considered in the analysis, 450 (59%) were ER+/PR+, 110 (14%) were ER+/PR–, and 199 (26%) were ER–/PR–.


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  		Table 1. Characteristics of Breast Cancer Cases (Joint Receptor Status Known) and Population Controls, Ontario, Canada, 2003–2005

 
Cases with ER+/PR– tumors were slightly older and more likely to be postmenopausal, be nulliparous, and to have never breastfed. A higher proportion of women with ER+/PR– and ER–/PR– tumors were of non-European heritage. Women with ER+/PR+ tumors were slightly more likely to report a first-degree family history of breast cancer.

We observed few and inconsistent differences in risk estimates regarding vitamin-D-related exposure variables (from diet and the sun) between subsets of patients defined by joint ER and PR status (Tables 2 and 3). Between the ages of 10 and 19 years, ever having taken cod liver oil was associated with a significantly reduced risk of ER+/PR+ tumors, although the estimates in ER+/PR– and ER–/PR– subgroups were comparable. The negative association for increasing milk consumption in adolescence and early adulthood was significantly different between all 3 tumor subgroups (P = 0.002 and P = 0.03, respectively), with a stronger reduced risk for ER+/PR+ tumors (P for linear trend = 0.003 and P for linear trend = 0.03, respectively). However, significant trends were observed for ER–/PR– tumors for both age groups (P = 0.02 and P = 0.01, respectively). Between the ages of 20 and 29 years, increased milk consumption also showed similar inverse associations for ER+/PR– tumors, and the P for trend approached significance (P = 0.05). The odds ratios for general vitamin supplement use (vitamin D/multivitamins and other) between the ages of 10 and 19 and 20 and 29 years were significantly different between tumor subgroups (P = 0.002 and P = 0.006, respectively), being more significantly associated with a reduced risk of ER+/PR+ tumors.


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  		Table 2. Fully Adjusted Odds Ratios and 95% Confidence Intervals for an Association Between Dietary and Supplement Vitamin D Intake at Specific Ages and Breast Cancer According to Joint Estrogen and Progesterone Receptor Status, Ontario, Canada, 2003–2005

 

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  		Table 3. Fully Adjusted Odds Ratios and 95% Confidence Intervals for an Association Between Vitamin-D-Related Sun Exposure Variables at Specific Ages and Breast Cancer According to Joint Estrogen and Progesterone Receptor Status, Ontario, Canada, 2003–2005

 
Table 3 shows the association between sun exposure variables and breast cancer by joint ER and PR status of the tumor. Between the ages of 10 and 19 years, the inverse association with increasing frequency of outdoor activities was more pronounced among women with ER+/PR+ and ER+/PR– tumors, and the P for trend was significant for both subgroups (P = 0.007 and P = 0.04, respectively); however, a significant difference in odds ratios among the 3 tumor subtypes was not observed (P = 0.12). A similar pattern was observed for increasing frequency of outdoor activities between the ages of 20 and 29 years. The reduced risk of breast cancer for women who reported ever working outdoors between the ages of 10 and 19 years was different across tumor subtypes (P = 0.003), showing a stronger reduced risk associated with both ER+/PR– and ER–/PR– tumors.

Between the ages of 10 and 19 and 20 and 29 years, a significant positive association and a significant P for trend were observed between degree of limb coverage and ER+/PR+ breast cancers (P for trend = 0.001 for both). Weaker positive associations were observed for ER+/PR– and ER–/PR– tumors, although the difference in estimates among the 3 tumor subgroups approached significance (age 10–19 years, P = 0.06; age 20–29 years, P = 0.05). Women whose skin did not darken or burn in adolescence had a significantly increased risk of ER+/PR+ tumors, although the odds ratio was not significantly different from that for the other tumor subtypes (P = 0.13).

Examination of vitamin-D-related exposures (from the sun and diet) among women with and without information on ER and PR status revealed no significant differences (data not shown). We further observed no significant differences in the results between premenopausal and postmenopausal women or between women who used and did not use hormone therapy (ever vs. never users) (data not shown). Results for ER+/PR+ tumors were similar to those for ER+ and PR+ cases alone, and those for ER–/PR– tumors were similar to results for ER– and PR– cases alone (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this study, vitamin D from dietary intake and sun exposure during adolescence and early adulthood was most consistently associated with a reduced risk of ER+/PR+ tumors, possibly because this subgroup was the largest. However, some significant and nonsignificant inverse associations were also observed for receptor-negative (ER–/PR–) and/or mixed (ER+/PR–) tumors.

The epidemiologic evidence to date regarding vitamin D intake and hormone-receptor-defined breast cancer is limited and conflicting (13–16). In the Cancer Prevention Study II Nutrition Cohort, a stronger inverse relation was observed between increased dietary vitamin D intake (>300 IU/day vs. ≤100 IU/day) and ER+ postmenopausal breast cancer; however, for total vitamin D (diet plus supplements), no association was found with increasing intake (13). Results were similar when combined ER/PR status was considered (i.e., ER+/PR+ was similar to ER+ alone, and ER–/PR– was similar to ER–). Conversely, in the Iowa Women's Health Study, for postmenopausal women, a stronger, nonsignificant inverse association was observed for the highest versus lowest groups of total vitamin D intake (≥800 IU/day vs. <400 IU/day) among women with ER–/PR– tumors (15). In the Women's Health Study, higher intake of total vitamin D (in quintiles) was associated with a reduced risk of developing ER+ or PR+ tumors among premenopausal women only (14). Janowsky et al. (16) found that the risk associated with levels of 1,25(OH)2D in whole blood below the median value was higher for receptor-positive (ER and/or PR present) than receptor-negative (neither receptor present) breast cancers.

In contrast to previous studies, we considered vitamin D intake from specific dietary sources separately in our analysis. Milk contributes about 100 IU of vitamin D per glass (22), and milk drinking during adolescence and early adulthood did contribute more strongly to a reduced risk of ER+/PR+ tumors, although weaker inverse associations were observed for ER–/PR– tumors. Salmon and tuna provide approximately 360 IU per serving and 200 IU per serving (Office of Dietary Supplements, National Institutes of Health (http://ods.od.nih.gov/factsheets/vitamind.asp)), respectively; however, we did not observe an association with any tumor subgroup, likely because these fish were rarely eaten more than once a week. We only crudely assessed vitamin D supplement use and found that vitamin use in general during adolescence and early adulthood was associated with a reduced risk of ER+/PR+ tumors. Since we examined exposures earlier in life, we did, however, consider cod liver oil, a traditional source of vitamin D particularly for children, which provides about 400 IU per teaspoon (5 mL) (4). Although we observed a significantly reduced risk of ER+/PR+ tumors when cod liver oil was taken earlier in life, similar inverse associations were found for the other 2 tumor subgroups. Previous studies likely did not ask about cod liver oil because they focused on dietary intake later in life (i.e., age 45 years or older) (13–15). The original Nurses’ Health Study and Nurses’ Health Study II examined dietary intake of vitamin D during high school, but neither considered hormone receptor status of the tumor and did not consider cod liver oil (23, 24).

Sun exposure is a major source of vitamin D, and a maximal dose (~20,000 IU) can be obtained from a slight reddening of the skin (1 minimal erythemal dose) in less than 0.5 hours for light-colored skin, although a longer time is required for darker skin (25). In contrast to most other studies, we asked about summer sun exposure behaviors since, at northern latitudes, vitamin D is produced at this time only (5, 6). Similar to our dietary findings, greater sun exposure earlier in life (i.e., outdoor activities/job, degree of limb coverage, whether skin burned/darkened) was more consistently associated with a reduced risk of ER+/PR+ tumors, but comparable significant and nonsignificant estimates were found for women with ER–/PR– and/or ER+/PR– tumors. Previous studies that did not consider sun exposure may have missed associations between vitamin D and hormone-receptor-defined subgroups.

Two possible reasons could explain the conflicting evidence reported in the present and earlier studies. The first is the possibility of inadequate statistical power due to the small number of cases within strata defined by hormone receptor status, especially among receptor-negative tumors, which constitute a minority of breast cancers diagnosed (20). Of all studies, those by McCullough et al. (13) and Robien et al. (15) included the largest number of receptor-negative cases (n = 227 and n = 274, respectively); however, in the first study, ER status was available for only 53% of the population, whereas, in the second study, joint receptor status was available for 68% of the population. In the Women's Health Study, the number of cases with ER– and PR– tumors was even smaller, particularly among premenopausal women (n = 59 and n = 74, respectively), but the overall proportion of cases with known ER and PR status was high (95%) (14). The study by Janowsky et al. (16) had both a small proportion of cases whose receptor status was known (56%) and a very small number of receptor-negative cases (n = 21). In our study, receptor status was available for 80% of cases, and we had a slightly larger number of ER– and PR– cases (ER–, n = 206; PR–, n = 309; and ER–/PR–, n = 199) compared with some studies (14, 16).

Second, although an inverse relation between vitamin D and breast cancer is evident, vitamin D may not affect the risk of developing a specific type of hormonally defined breast cancer. Some data support the concept that the antiproliferative and antitumor effects of vitamin D and its analogues (e.g., EB1089) on estrogen-responsive breast cancer cells (ER+) are mediated via disruption of estrogen mitogenic and survival signals (8, 9). However, more recent studies of intracellular signaling in ER– breast cancer cell lines with a functional vitamin D receptor (e.g., SUM-159PT) have shown that vitamin D and its analogues can inhibit proliferation and induce growth arrest and apoptosis in these cells as well (26, 27). Hence, even though the estrogen signaling pathway is disrupted, sensitivity to the effects of vitamin D is maintained during the progression from an estrogen-dependent to an estrogen-independent state via the presence of the vitamin D receptor (26, 27).

This study has several strengths and limitations worth noting. Strengths include the consideration of potential markers of vitamin D synthesis from sun exposure as well as exposures earlier in life and risk of hormone-receptor-defined breast cancer. Joint ER and PR status was also available for 80% of cases, and we were able to examine associations among women with ER+/PR– tumors in addition to receptor-positive and -negative cases. However, the number of ER–/PR– and ER+/PR– tumors was still relatively small, although significant associations were observed in a few cases. Some findings may also be subject to chance because of the many analyses performed. Accuracy of recall, especially for early-life exposures, is a concern in any case-control study, although several studies have found evidence that sun exposure, both recent and in childhood and adolescence, could be recalled reasonably consistently (28). Recent studies, including our own, comparing responses to vitamin-D-related questions (from the sun and/or diet) to circulating levels of 25(OH)D showed significant associations between recent exposures and 25(OH)D levels (28, 29). Biased recall between cases and controls is also a concern, although differential recall between cases with differing hormone-defined breast cancer is unlikely. At the time our study was conducted, there was little media attention regarding a potential relation between vitamin D or sun exposure and breast cancer (17).

To conclude, we previously reported an inverse relation between increased vitamin D intake from the sun and diet, especially during adolescence and early adulthood, and overall breast cancer risk (17). In the present study, results suggest that vitamin D intake early in life influences breast cancer risk regardless of ER/PR receptor status. Although significant estimates were most consistently found for women with receptor-positive cancers (ER+/PR+), the largest subgroup, similar nonsignificant and significant associations were at times observed for receptor-negative and mixed tumors. Future studies should include a larger number of women with receptor-negative cancers.


   ACKNOWLEDGMENTS
 
Author affiliations: Prosserman Center for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada (Kristina M. Blackmore, Maia Lesosky, Heidi Barnett, Janet M. Raboud, Julia A. Knight); Department of Public Health Sciences, University of Toronto, Toronto, Canada (Janet M. Raboud, Julia A. Knight); University Health Network, Toronto, Canada (Janet M. Raboud); Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada (Reinhold Vieth); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada (Reinhold Vieth).

This research was funded by the Canadian Breast Cancer Research Alliance (grant 14583).

The authors thank Ansley Wong, Jody Wong, and Sutha Shanmugarajah for their contributions to data collection.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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Vitamin D and Risk for Breast Cancer According to Hormone-Receptor Status
Journal Watch Women's Health, November 13, 2008; 2008(1113): 1 - 1.
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