Vitamin D and breast cancer: insights from animal models.

1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3[, the biologically active form of vitamin D that interacts with the vitamin D receptor (VDR), is a coordinate regulator of proliferation, differentiation, and survival of breast cancer cells. Therefore, vitamin D compounds that bind and activate VDRs offer promise as therapeutic agents for the treatment of established breast cancer. In addition, epidemiologic, clinical, and animal studies suggested that vitamin D status is important for protection against the development of breast cancer. To elucidate potential biological mechanisms through which vitamin D status might be associated with breast cancer risk, basic research studies focused on defining the molecular effects of vitamin D signaling in the normal mammary gland. Both VDR and vitamin D 1-hydroxylase, the enzyme that generates 1,25(OH)2D3, are expressed and dynamically regulated in the normal mammary gland. Furthermore, studies with mice lacking VDRs established that vitamin D participates in negative growth control of the normal mammary gland and that disruption of VDR signaling is associated with abnormal ductal morphologic features, increased incidence of preneoplastic lesions, and accelerated mammary tumor development. These studies support the concept that suboptimal generation of 1,25(OH)2D3 in the mammary gland might sufficiently deregulate VDR-mediated gene expression to sensitize mammary cells to transformation. In light of these observations, studies to define the most appropriate biomarkers of vitamin D status in relation to protection against breast cancer among human subjects are urgently needed.