Mammographic density has consistently been shown to be one of the strongest risk factors for breast cancer. Women with 75% or more breast density are at a 4 to 6-fold greater risk of breast cancer than women with no density. It has been hypothesized that mammographic density is the reflection of cumulative estrogen exposure, despite the fact that there are no direct data supporting this. Our preliminary data, and accumulating evidence suggest that the mechanism by which mammographic density influences breast cancer is independent of circulating estrogen levels. There is increasing ecologic, epidemiologic and biologic data implicating the vitamin D pathway in breast carcinogenesis, making it a compelling potential mediator of the mammographic density-breast cancer relation. In the Nurses' Health Study cohort, we found a non-significant inverse association between plasma levels of vitamin D metabolites, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and breast cancer in a nested case-control study with 701 cases and 724 controls. In the same group of women, we also found an association between the Fokl polymorphism in the vitamin D receptor and breast cancer. We propose to conduct a cross-sectional analysis to examine the vitamin D-mammographic density relationship among controls in the nested case-control study described above. All laboratory assays, genotyping and measurements of mammographic density have already been conducted as part of prior studies. This is an efficient study design to examine the role of vitamin D and mammographic density in existing data. We specifically hypothesize that: 1.) Plasma levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are inversely associated with percent mammographic density, and 2.) Polymorphisms in the vitamin D receptor gene are associated with mammographic density. In addition, we will explore if the vitamin D-mammographic density relationship is modified by polymorphisms in the vitamin D receptor. Given that vitamin D levels are readily modifiable and that mammographic density is a noninvasive intermediate marker of breast cancer this proposal has important implications for breast cancer prevention. [unreadable] [unreadable] [unreadable]