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Multiple epidemiological studies have demonstrated correlations between vitamin D status and incidence of many types of cancer, including colon and breast. Our long term goal is to understand the mechanisms by which the vitamin D signaling pathway impacts on breast cancer. Upon absorption or endogenous synthesis, vitamin D is metabolized into 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in multiple tissues. 1,25D is a high-affinity ligand for the nuclear vitamin D receptor (VDR) that alters gene expression and inhibits growth of normal and transformed mammary cells. However, 25D and other steroid-like compounds such as bile acids, can also activate VDR in vitro. Although studies with VDR knockout (KO) mice have demonstrated that VDR affects proliferation, differentiation and apoptosis in the mammary gland, the specific ligands that trigger VDR signaling in mammary tissue have yet to be identified. Generation of 1,25D from 25D is mediated by the mitochondrial enzyme CYP27B1 (also known as 25-hydroxyvitamin D 1α-hydroxylase) which is present and developmentally regulated in mammary gland. Studies with the VDRKO mouse have formally established that its phenotype is different from mice lacking CYP27B1, supporting the concept that other VDR ligands exist, and/or that the VDR may act in the absence of ligand. In our studies, we are using animal models to determine whether VDR exerts 1,25D-independent effects on growth, apoptosis or differentiation of mammary epithelial cells in vivo. Glands from VDRKO and CYP27B1KO mice during puberty, pregnancy, lactation, involution and aging have been collected for analysis of gross morphology, histology, and genomic profiling in comparison to age-matched control mice. Our data indicate that mammary glands from VDRKO mice display accelerated branching, enhanced sensitivity to estrogen and progesterone and altered gene expression during puberty and early pregnancy. Surprisingly, initial studies indicate that similar changes are not observed in glands from CYP27B1KO mice, suggesting that 25D or other VDR ligands may substitute for 1,25D in control of mammary cell turnover in vivo. Alternatively, our results are consistent with the concept that unoccupied VDR may function in the mammary gland. To further explore the role of VDR and CYP27B1 in the glandular epithelial compartment, mice with mammary epithelial-specific deletion of VDR or CYP27B1 were generated by crossing MMTV-cre mice with mice carrying floxed alleles of VDR or CYP27B1. Quantitation of VDR and CYP27B1 expression in mammary gland, and characterization of the phenotype of these cre-flox mouse strains is in progress. Collectively, these studies have identified novel roles for the VDR and its ligands in mammary gland development that provide insight into the relationship between vitamin D status and breast cancer. Supported by NIH CA69700. Citation Information: Cancer Res 2009;69(23 Suppl):A41.