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American Journal of Epidemiology Advance Access originally published online on October 12, 2007
American Journal of Epidemiology 2007 166(12):1409-1419; doi:10.1093/aje/kwm259
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Sun Exposure, Vitamin D Receptor Gene Polymorphisms, and Breast Cancer Risk in a Multiethnic Population

Esther M. John1,2, Gary G. Schwartz3, Jocelyn Koo1, Wei Wang4 and Sue A. Ingles4

1 Northern California Cancer Center, Fremont, CA
2 Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA
3 Departments of Cancer Biology and Epidemiology and Prevention, Wake Forest University, Winston-Salem, NC
4 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA

Correspondence to Dr. Esther M. John, Northern California Cancer Center, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538 (e-mail: ejohn{at}nccc.org).

Received for publication February 7, 2007. Accepted for publication July 26, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Considerable evidence indicates that vitamin D may reduce the risk of several cancers, including breast cancer. This study examined associations of breast cancer with sun exposure, the principal source of vitamin D, and vitamin D receptor gene (VDR) polymorphisms (FokI, TaqI, BglI) in a population-based case-control study of Hispanic, African-American, and non-Hispanic White women aged 35–79 years from the San Francisco Bay Area of California (1995–2003). In-person interviews were obtained for 1,788 newly diagnosed cases and 2,129 controls. Skin pigmentation measurements were taken on the upper underarm (a sun-protected site that measures constitutive pigmentation) and on the forehead (a sun-exposed site) using reflectometry. Biospecimens were collected for a subset of the study population (814 cases, 910 controls). A high sun exposure index based on reflectometry was associated with reduced risk of advanced breast cancer among women with light constitutive skin pigmentation (odds ratio = 0.53, 95% confidence interval: 0.31, 0.91). The association did not vary with VDR genotype. No associations were found for women with medium or dark pigmentation. Localized breast cancer was not associated with sun exposure or VDR genotype. This study supports the hypothesis that sunlight exposure reduces risk of advanced breast cancer among women with light skin pigmentation.

African Americans; breast neoplasms; Hispanic Americans; polymorphism, genetic; receptors, calcitrol; skin pigmentation; sunlight; vitamin D

Abbreviations: CI, confidence interval; OR, odds ratio; VDR, vitamin D receptor; 25(OH)D, 25-hydroxyvitamin D (calcidiol); 1,25(OH)2D, 1,25-dihydroxyvitamin D (calcitriol)


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Vitamin D status is a modifiable factor that may reduce breast cancer risk (1–3). In the United States, breast cancer mortality rates are higher in the Northeast than in the South (4) and are inversely correlated with solar radiation levels (5). On the basis of this geographic variation, Garland et al. hypothesized that vitamin D reduces breast cancer mortality (6), as was proposed previously for cancers of the colon (7) and prostate (8).

Exposure to ultraviolet radiation accounts for 90 percent of 25-hydroxyvitamin D (25(OH)D, calcidiol), the major circulating vitamin D metabolite, which is the substrate for 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol), the biologically most active form of vitamin D (3). 25-hydroxyvitamin D1{alpha}-hydroxylase, the enzyme that converts 25(OH)D to 1,25(OH)2D in the kidney, also is expressed in many nonrenal tissues (9), including breast (10), raising the possibility of intracrine or paracrine 1,25(OH)2D synthesis within the breast. Extensive experimental data demonstrate that 1,25(OH)2D induces differentiation and apoptosis, and it inhibits invasion and metastasis in breast and other cells (11–13). The effects of 1,25(OH)2D are mediated by the vitamin D receptor (VDR), which is expressed in breast and many other tissues (11). The expression and/or function of the VDR protein may be influenced by polymorphisms in the VDR gene.

A relation between vitamin D and breast cancer is supported by several, but not all, epidemiologic studies (14, 15). In non-Hispanic White women, reduced risk has been associated with high early-life residential solar radiation (16), usual residence in a region of high solar radiation (16), frequent outdoor activity at ages 10–19 years (17), frequent adult recreational or occupational sun exposure (16), high dietary vitamin D intake (18–20), and high serum levels of 25(OH)D (21, 22). High residential and occupational sun exposure has been associated with lower breast cancer mortality (23). Several studies reported associations of breast cancer risk with VDR gene polymorphisms (22, 24–27).

We examined associations of breast cancer with sun exposure and VDR polymorphisms in a large, population-based case-control study in a multiethnic population with a wide range of capacity for cutaneous production of vitamin D.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
Hispanic, African-American, and non-Hispanic White women aged 35–79 years and newly diagnosed with a first primary invasive breast cancer between 1995 and 1999 were identified through the California population-based Greater Bay Area Cancer Registry, which ascertains all incident cancers as part of the Surveillance, Epidemiology, and End Results program. Of 10,159 identified cases, 11 percent could not be contacted (392 were deceased, 51 had physician refusals, 55 were Asian American per physician report, 600 were lost to follow-up or had moved, and six declined participation in any study), and 8,043 (90 percent of those contacted) completed a brief telephone screening interview that assessed study eligibility and self-identified race/ethnicity. All Hispanics and African Americans, and a 10 percent random sample of non-Hispanic Whites, were selected into the study (n = 2,054), and 1,788 (87 percent) completed the in-person interview, including 649 (88 percent) Hispanics, 543 (87 percent) African Americans, and 596 (86 percent) non-Hispanic Whites. A subset of cases (diagnosed between 1997 and 1999) were recontacted, and blood or mouthwash samples were obtained for 814 (88 percent) who completed the interview, including 287 (88 percent) Hispanics, 250 (85 percent) African Americans, and 277 (90 percent) non-Hispanic Whites.

Population controls aged 35–79 years were identified through random digit dialing, described elsewhere (28). Of 108,007 random numbers called as many as 10 times, 42,885 were nonresidential, 4,817 were reached by an answering machine only, and 9,920 remained unanswered. For the remaining 50,385 numbers, where a household member was reached, a household enumeration was completed for 41,427 (82 percent). From the pool of eligible women, 2,999 were randomly selected by frequency matching on race/ethnicity and 5-year age group. Of these, 6 percent could not be contacted (14 were deceased, 170 were lost to follow-up or had moved), and 2,574 (91 percent of those contacted) completed the telephone screening interview. Of 2,523 eligible controls, 2,129 (84 percent) participated in the study, including 885 (87 percent) Hispanics, 598 (82 percent) African Americans, and 646 (83 percent) non-Hispanic Whites. Among those recontacted for biospecimen collection, 910 (87 percent) provided a sample, including 357 (85 percent) Hispanics, 255 (84 percent) African Americans, and 299 (93 percent) non-Hispanic Whites.

Data collection
Trained interviewers administered a structured questionnaire in English or Spanish on hormonal and lifestyle factors, including lifetime histories of outdoor activities (outdoor sports and exercise, walking and bicycling for transportation, gardening and other outdoor chores, and outdoor occupational activity), that assessed for each episode of outdoor activity the ages at which the activity started and ended and the duration of the activity (hours per week). The interview also asked about summertime outdoor activity (hours per week) at ages 10–15 years, 25–30 years, and 50–55 years. Using a portable reflectometer (Minolta Chromameter CR-300, Osaka, Japan), the interviewers took two measurements each of skin pigmentation at the upper underarm, a site generally not exposed to sunlight (constitutive pigmentation), and at the center of the forehead, a site generally exposed to sunlight (facultative pigmentation). The Chromameter measures skin color through skin reflectance, which ranges from 0 (perfect black) to 100 (perfect white). This instrument has been shown to quantify small skin-color changes (29) and to produce measurements of high intra- and interrater reproducibility (30). The difference between constitutive and facultative skin pigmentation has been proposed as a measure of cumulative sun exposure (31). Study participants provided written informed consent, and the institutional review boards at the Northern California Cancer Center and at the University of Southern California approved the study protocol.

VDR genotyping
Polymorphisms were examined in two regions of the VDR gene: a single nucleotide polymorphism in the first of two potential start codons in exon 2 (rs10735810, a FokI restriction fragment length polymorphism) and two single nucleotide polymorphisms in exon 9 (rs731236, a synonymous TaqI RFLP, and rs739837, a BglI restriction fragment length polymorphism lying 303 base pairs downstream of the stop codon). In exon 2, use of the second start codon, as occurs in the F polymorphic variant lacking the first start codon (32), results in a VDR protein with an activation domain shortened by three amino acids (33). This protein is more efficient at transactivating a vitamin D–regulated target gene (34). Because known polymorphisms in the 3' region of the VDR gene do not alter the amino acid sequence of the VDR protein, the functional significance of these variants is unclear. 3' Untranslated region sequence variants may interact differently with other upstream sequences in the VDR gene to regulate transcription, translation, or RNA processing (35, 36).

Genotyping of the three single nucleotide polymorphisms, FokI, TaqI, and BglI, was performed by the TaqMan assay using the TaqMan Core Reagent Kit (Applied Biosystems, Foster City, California). Polymerase chain reactions were carried out by using standard conditions recommended by the manufacturer. The following primer and minor groove binder probe sequences were used: for FokI, forward primer 5'-GCACTGACTCTGGCTCTGACCG-3', reverse primer 5'-GTCAAAGTCTCCAGGGTCAGGCA-3', A allele VIC-TTGCCTCCATCCCTGTAA-3', and G allele FAM-TGCCTCCGTCCCTGTA-3'; for TaqI, forward primer 5'-CTTCTCTATCCCCGTGCCC-3', reverse primer 5'-ACGTCTGCAGTGTGTTGGACA-3', T allele VIC-GCGCTGATTGAGGCCA-3', and C allele FAM-CGCTGATCGAGGCCA-3'; and for BglI, forward primer 5'-GCAGGGCCTTGCCCA-3', reverse primer 5'-CACTAGGCGCTGGACAAGC-3', C allele FAM-CGCTGCCTAAGTGG-3', and A allele VIC-CCGCTGCATAAGTGG-3'. Fluorescent signals were measured by using an ABI 7900HT Detection System (Applied Biosystems). Experimental samples were compared with nine previously sequenced controls (three of each genotype) to identify the three genotypes at each locus. Samples outside of the parameters defined by the controls were identified as noninformative. All polymerase chain reaction batches included water blanks. Technicians were blinded to case-control status. There were no discrepancies among 75 duplicate samples.

For consistency with previous literature, genotypes for the three restriction fragment length polymorphisms are reported here using standard nomenclature. The FokI A and G alleles are indicated by f and F, respectively; the TaqI T and C alleles by T and t, respectively; and the BglI A and C alleles by B and b, respectively.

Exposure variables
Measures of sun exposure included summary variables for outdoor activities (at ages 10–19 years, 20–39 years, and ≥40 years, and average lifetime); summertime outdoor activity (at ages 10–15 years, 25–30 years, and 50–55 years); and three measures derived from the skin pigmentation measurements, including constitutive skin pigmentation (which affects the ability to synthesize vitamin D), facultative skin pigmentation, and a sun exposure index (the difference between facultative and constitutive pigmentation divided by constitutive pigmentation multiplied by 100) (31). In addition, we considered the absolute difference between facultative and constitutive pigmentation.

Statistical analysis
We used unconditional logistic regression to estimate odds ratios and 95 percent confidence intervals associated with sun exposure measures and VDR genotype. Because the skin's capacity to form vitamin D is strongly influenced by constitutive pigmentation (37), we performed separate analyses for women with light, medium, and dark constitutive pigmentation (categorized according to the tertile distribution among controls). Potential confounding was evaluated separately for each pigmentation group for the following variables: age, race/ethnicity, education, family history of breast cancer in first-degree relatives, personal history of benign breast disease, age at menarche, number of full-term pregnancies, breastfeeding, menopausal status, hormone therapy use, body mass index based on measured height and self-reported weight during the reference year (defined as the calendar year prior to diagnosis for cases or prior to selection into the study for controls), height, average lifetime physical activity (described elsewhere (John et al. (28)), and alcohol consumption in the reference year. The variables were categorized as shown in table 1. Variables significantly associated with breast cancer risk in this data set were included in logistic regression models, as noted in the footnotes of the tables. Age-adjusted and multivariate-adjusted odds ratio estimates generally were similar; thus, only multivariate-adjusted results are shown. The pigmentation-based analyses were also adjusted for the month in which the measurements were taken. Dose-response trends were assessed across ordinal values of categorical variables.


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  		TABLE 1. Characteristics of the study population, by case-control status, San Francisco Bay Area Breast Cancer Study, California, 1995–2003*

 
Because vitamin D may have different effects on both differentiation (early-stage disease) and metastases (late-stage disease) (38), we performed separate analyses for localized and advanced (regional and distant stage) breast cancer. To explore the modifying effect of sun exposure on the association between VDR genotype and breast cancer risk, we stratified the analyses by the sun exposure index (below and above the median). To determine whether variation at the 3' locus acts differently in combination with the two FokI alleles (35), we categorized FokI/TaqI genotype combinations by number of high-activity (FokI F, TaqI t) alleles. Tests of interaction were performed by including cross-product terms in the logistic models and conducting a one degree of freedom Wald test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
One third of interviewed cases were diagnosed with advanced breast cancer (regional or distant stage). Both advanced and localized cases were interviewed approximately 1 year following diagnosis (advanced cases: median, 14.5 months and range, 6.6–47.2; localized cases: median, 14.5 months and range, 5.4–44.8). Compared with controls, cases were more likely to have been born in the United States, have a college education, have a family history of breast cancer, have a personal history of benign breast disease, reach menarche at a young age, have no or few full-term pregnancies, experience their first full-term pregnancy at a late age, have no or a short duration of breastfeeding, have a low body mass index (among premenopausal women), be tall, have low levels of physical activity, and consume high levels of alcohol (table 1).

Among controls, scores for constitutive skin pigmentation (upper underarm) ranged from 7.5 (dark) to 93.9 (light); facultative pigmentation (forehead) scores ranged from 7.5 to 85.4 (table 2). The correlation between the two measurements taken at each site was high (r = 0.985 and r = 0.983, respectively). When controls were categorized according to their tertile distribution of constitutive pigmentation (light, medium, dark), the sun exposure index differed significantly between the three pigmentation groups, with the highest index in the light pigmentation group. Self-reported lifetime outdoor activity and outdoor activity during the reference year were also highest among controls with light pigmentation, although the differences between the three pigmentation groups were not statistically significant (p = 0.57 and p = 0.17, respectively). Self-identified race/ethnicity over-lapped between the three pigmentation groups, with representation of all three racial/ethnic groups in each pigmentation group. Non-Hispanic Whites predominated in the light pigmentation group (65 percent); Hispanics and African Americans had the highest representation in the medium (68 percent) and high (75 percent) pigmentation groups, respectively.


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  		TABLE 2. Skin pigmentation, sun exposure index, and lifetime outdoor activity among controls, by constitutive skin pigmentation, San Francisco Bay Area Breast Cancer Study, California, 1995–2003

 
Lifetime outdoor activity was not associated with advanced or localized breast cancer in any of the three pigmentation groups (table 3). In addition, for both outdoor activity at ages 10–19 years or 20–29 years or summertime outdoor activity at ages 10–15 years or 25–30 years, there was no evidence that high outdoor activity was associated with reduced risk (data not shown).


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  		TABLE 3. Outdoor activity, skin pigmentation, sun exposure index, and risk of breast cancer, by constitutive skin pigmentation and stage at diagnosis, San Francisco Bay Area Breast Cancer Study, California, 1995–2003

 
Constitutive skin pigmentation did not vary significantly between advanced cases and controls in any of the three pigmentation groups (table 3). Increasing facultative pigmentation was associated with a trend of decreasing risk of advanced breast cancer for only those women with light pigmentation (p = 0.02). For these women, risk of advanced breast cancer decreased with increasing sun exposure index (p trend = 0.01). Among those with the highest sun exposure index, risk was reduced by 47 percent (odds ratio (OR) = 0.53, 95 percent confidence interval (CI): 0.31, 0.91; p = 0.02). Similar risk reductions were seen when we compared controls with cases who had their skin pigmentation measured within 14 months of diagnosis (OR = 0.41, 95 percent CI: 0.20, 0.83 for the highest vs. lowest tertile) and cases measured more than 14 months after diagnosis (OR = 0.64, 95 percent CI: 0.35, 1.17). Risk reductions were similar among study participants with pigmentation measurements taken during the summer (April to October) (OR = 0.53, 95 percent CI: 0.29, 0.98 for the highest vs. lowest tertile) and those taken during the winter (November to March) (OR = 0.47, 95 percent CI: 0.21, 1.05 for the highest vs. lowest tertile). In contrast, no associations were observed for localized breast cancer with any of the pigmentation measures (table 3). Considering the absolute difference between facultative and constitutive pigmentation did not alter the results (data not shown).

The VDR genotypes were in Hardy-Weinberg equilibrium for all three markers (p ≥ 0.05). We found no evidence of associations between VDR genotype and advanced or localized breast cancer risk in any of the three pigmentation groups, except for the BglI BB genotype, which was associated with a significant decrease in advanced disease among women with medium pigmentation (OR = 0.37, 95 percent CI: 0.18, 0.76) (table 4). Stratifying the analyses by race/ethnicity instead of facultative pigmentation produced similar results of no association (data not shown). In women with light pigmentation, VDR genotype did not modify the inverse association of advanced breast cancer with high sun exposure index. When we compared women with a high index with women with a low index (above vs. below the median), risk was reduced by 54 percent (OR = 0.46, 95 percent CI: 0.26, 0.79), with little variation by BglI genotype (OR = 0.41, 95 percent CI: 0.20, 0.85 for the Bb or bb genotype; OR = 0.45, 95 percent CI: 0.18, 1.13 for the BB genotype) or TaqI genotype (OR = 0.46, 95 percent CI: 0.25, 0.86 for the TT or Tt genotype; OR = 0.36, 95 percent CI: 0.10, 1.32 for the tt genotype). When we stratified by FokI genotype, odds ratios were 0.35 (95 percent CI: 0.17, 0.71) and 0.72 (95 percent CI: 0.29, 1.82) for the ff or Ff genotype and for the FF genotype, respectively.


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  		TABLE 4. VDR* genotype and breast cancer risk,{dagger} by constitutive skin pigmentation and stage of disease, San Francisco Bay Area Breast Cancer Study, California, 1995–2003

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this population-based case-control study, a high sun exposure index was associated with a lower risk of advanced, but not localized, breast cancer. An inverse association with advanced breast cancer was observed for only those women with light constitutive pigmentation; a high index (highest vs. lowest quartile) reduced risk by 47 percent. There was no evidence that VDR genotype modified this inverse association.

Accurate assessment of the biologically effective dose of ultraviolet radiation with respect to vitamin D synthesis is challenging because many factors, both environmental (e.g., latitude, season, altitude, time of day, cloud cover, air pollution) and personal (e.g., constitutive skin pigmentation, age, clothing, and sunscreen use), modify vitamin D synthesis (39). Most prior studies estimated ultraviolet radiation exposure inferred from residential history (16, 23) and self-reported frequency of sun exposure (16) or outdoor activity (17, 18). We assessed differences between constitutive and facultative skin pigmentation, which is a known response to sun exposure and therefore an objective measure of past sun exposure. This index has been proposed as a measure of cumulative sun exposure (31), and we previously used it in a report of an inverse association with advanced prostate cancer (40). Facultative pigmentation has been shown to vary with residential solar radiation levels (41). Our data show that skin pigmentation can be measured with high intrarater reproducibility. Importantly, unlike sun exposure measured by self-report, the pigmentation-based sun exposure index is not subject to recall bias.

Our results should be interpreted in light of several potential limitations. Assessing the sun exposure index after diagnosis raises the possibility that advanced cases could have spent less time outdoors because of their illness. However, the risk reductions we observed were of similar magnitude for cases whose pigmentation measurements were made within or after 14 months of diagnosis, suggesting that "reverse causality" does not explain these findings. Nonetheless, further work validating the sun exposure index would be valuable. To our knowledge, no studies have examined the relation between the pigmentation-based sun exposure index and serum 25(OH)D levels. Although the major source of circulating 25(OH)D levels is sun exposure, the relation with dietary and supplemental vitamin D intake warrants investigation and will be reported separately. Retrospective assessment of past outdoor activity may be limited by recall bias but is unlikely to be differential between cases and controls because the interview did not specifically focus on sun exposure. Finally, selection bias due to nonresponse is a possibility, but response rates were similarly high for cases and controls in all three racial/ethnic groups, and associations with established risk factors shown in table 1 agree with those in the epidemiologic literature (42).

Several epidemiologic observations support a protective role for vitamin D on breast cancer risk. In US studies with wide variation in ultraviolet radiation levels, high residential solar radiation was inversely associated with breast cancer mortality (23) and risk of developing breast cancer (16). Two studies assessed breast cancer risk in relation to personal sun exposure history: in the First National Health and Nutrition Examination Survey follow-up study, risk was 30–35 percent lower for women with considerable sun exposure (determined by their physician) and for those who self-reported frequent (vs. rare or never) recreational and occupational sun exposure (16). Frequent outdoor activity at ages 10–19 years was associated with a 45 percent risk reduction for Canadian women (17). Occupational sun exposure derived from job titles was associated with an 18 percent reduction in mortality in a national death certificate–based study (23). Conversely, no association with self-reported outdoor activity was found in the Nurses' Health Study (18). The present study also found no evidence of lower risk for women with high outdoor activity during the lifetime or at specific ages. Self-reported lifetime outdoor activity may be insufficiently precise to capture the biologically effective dose of ultraviolet radiation needed to produce vitamin D. For example, not all sunlight exposure is equal (43, 44); vitamin D synthesis is strongly influenced by geographic latitude, season, and time of day (45).

Our finding of an inverse association of sun exposure with advanced but not localized disease is in agreement with findings from our recent population-based case-control study of prostate cancer, in which we used a similar methodology to assess past sun exposure (40). We reported an inverse association between the pigmentation-based sun exposure index and advanced prostate cancer that was of similar magnitude (OR = 0.51, 95 percent CI: 0.33, 0.80 for the highest vs. lowest quintile) (40), but we found no association with localized disease (unpublished data). This finding is consistent with several epidemiologic observations suggesting a role for sun exposure that is stronger for advanced than localized breast cancer. A recent study conducted in England reported lower serum 25(OH)D levels in breast cancer cases with advanced disease than those with early-stage disease (46). Similarly, in the present study, among women with light pigmentation, cases with advanced disease had a slightly lower sun exposure index (21.9) than those with localized disease (23.1) or controls (23.3). Recent data suggest that seasonal variation in ultraviolet radiation at the time of diagnosis may affect survival from breast and other cancers (47–49).

To our knowledge, this is the first analytic study to examine sun exposure and breast cancer risk in African Americans and Hispanics. A large national survey has shown that serum 25(OH)D levels are lowest in African Americans, intermediate in Hispanics, and highest in non-Hispanic Whites (50), which is consistent with the generally decreasing pigmentation in these groups (37). We stratified the study population by constitutive skin pigmentation as a surrogate for their capacity to produce vitamin D. We believe that, with respect to vitamin D synthesis, stratification by constitutive skin pigmentation (an objective, physical measure) is a biologically more relevant parameter than race/ethnicity (by self-report) and is less subject to respondent bias. In the present study, we found significant differences between cases and controls regarding their pigmentation-based sun exposure index in only the light pigmentation group. It is possible that, in more heavily pigmented persons, the sun exposure index used in this study is a less sensitive measure of past sun exposure and/or that, in these women, such exposure generated less vitamin D (51).

A complementary approach to studying the effects of vitamin D involves examination of VDR gene polymorphisms. Our genotyping was limited to three polymorphisms, including a known functional variant (FokI). Although several studies (24–26, 52) found no evidence for an association with the FokI polymorphism, the largest known study conducted to date, of mostly non-Hispanic White women (27), found the FokI ff (vs. FF) genotype to be associated with a significantly increased risk (OR = 1.34, 95 percent CI: 1.06, 1.69). We found no associations with VDR genotype, but our study included relatively few cases with light pigmentation, the group that appears to benefit from sunlight exposure.

In conclusion, the present findings add to the growing body of evidence that vitamin D plays a role in the natural history of breast cancer. If confirmed by other studies, our finding of a decreased risk for advanced but not localized breast cancer cases has significant public health implications. In particular, if sun exposure reduces the risk of tumor progression, vitamin D could be recommended for women diagnosed with localized breast cancer. Further exploration of this finding and its implications is warranted.


   ACKNOWLEDGMENTS
 
This research was supported by grants (to E. M. J.) CA63446 and CA77305 from the National Cancer Institute, grant DAMD17-96-6071 from the United States Army Medical Research Program, and in part by grants (to W. W.) 8GB-0103 and 11FB-0133 from the California Breast Cancer Research Program. Cancer incidence data used in this paper were collected by the Greater Bay Area Cancer Registry, of the Northern California Cancer Center, under contract N01-PC-35136 with the National Cancer Institute, National Institutes of Health, and with support from the California Cancer Registry, a project of the Cancer Surveillance Section, California Department of Health Services, under subcontract 1006128 with the Public Health Institute.

Mention of trade names, commercial products, specific equipment, or organizations does not constitute endorsement, guarantee, or warranty by the State of California Department of Health Services or the US Government, nor does it imply approval to the exclusion of other products. The views expressed in this publication represent those of the authors and do not necessarily reflect the position or policies of the Northern California Cancer Center, the California Public Health Institute, the State of California Department of Health Services, or the US Department of Health and Human Services.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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