Epidemiological studies of vitamin D and breast cancer.

Abundant experimental evidence provides a rationale for examining the role of vitamin D in relation to breast cancer risk. Specifically, the main actions of the biologically active form of vitamin D, 1,25(OH)2D, are mediated via the vitamin D receptor. The vitamin D receptor (VDR) is present in normal breast tissue. 1,25(OH)2D has antiproliferative effects on and promotes the differentiation of breast cancer cells. In MCF-7 cells, vitamin D and vitamin D analogs have been shown to induce cell cycle arrest and apoptosis, to downregulate estrogen receptor expression, to limit responsiveness to the mitogenic effects of 17beta-estradiol, and to limit induction of the progesterone receptor. Epidemiologic evidence bearing on the relationship between vitamin D and breast cancer risk has come from several sources: ecologic studies, studies of vitamin D in relation to breast density, studies of VDR polymorphisms and breast cancer risk, studies of circulating vitamin D levels and risk, and studies of dietary and supplemental vitamin D intake and risk. There have been several ecologic studies of the association between sunlight or solar radiation exposure and breast cancer incidence or mortality. These are of interest because synthesis in the skin resulting from exposure to sunlight (in particular, exposure to UV-B radiation) is the major source of endogenous vitamin D production in humans, given that few food sources contain vitamin D. For example, one study showed a strong inverse association between per capita average annual total solar energy exposure (calories/cm/d) and breast cancer incidence rates in republics of the former Soviet Union. However, as is well known, ecologic studies suffer from a number of limitations, including the fact that because measurements are averaged over individuals, associations observed at the population level may not reflect associations at the individual level and generally do not account for potential confounding. Therefore, this type of information is suggestive (hypothesis-generating) at best. Mammographic (breast) density reflects the epithelial and stromal components of the breast; fat appears dark and epithelium and stroma appear light or white. Women with very dense breast tissue, as seen on mammography, are at increased risk of subsequent breast cancer. Mammographic density can be modified, and such changes represent a potential biological marker for assessing the effects of dietary/supplemental factors on breast cancer risk. Four studies have examined the association between vitamin D and breast density. Of these, two showed an inverse association between vitamin D intake and breast density in premenopausal women only (one focused on vitamin D from foods only and the other on total vitamin D intake from foods and supplements), one study showed an inverse association in both premenopausal and postmenopausal women (dietary vitamin D only), and one study showed no association. However, all of these studies were cross-sectional, which limits the inferences that can be drawn. Interestingly, in one study, the association was independent of sunlight exposure but weakened after adjustment for calcium intake, highlighting the need to include assessment of calcium intake in studies of vitamin D. A recent cross-sectional study showed no association between serum 25-hydroxyvitamin D levels and mammographic density. The vitamin D receptor is a nuclear transcription regulating factor that is the crucial mediator of the cellular growth and differentiation effects of vitamin D. It is expressed in normal and malignant breast cells. Genetic polymorphisms in the VDR might influence breast cancer risk due to their effects on VDR gene expression and protein function. Of the polymorphisms that have been identified in the VDR gene (largely through their restriction endonuclease cleavage sites), Fok1, Bsm1, Apa1, Taq1, and Poly(A) have been studied most frequently. Whereas the Fok1 polymorphism (a T-to-C transition in exon 2) has functional consequences, the functional significance of the Bsm1, Apa1, Taq1, and Poly(A) polymorphisms, located at the 3 end of the Dr. Rohan is with the Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA. Please address all correspondence to: Dr. Tom Rohan, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA; Phone: 718-4303355; Fax: 718-430-8653; E-mail: rohan@aecom.yu.edu. doi: 10.1301/nr.2007.aug.S80–S83