Vitamin D3 signaling and breast cancer: Insights from transgenic mouse models

Abstract The biologically active form of vitamin D 3 (1,25(OH) 2 D) regulates epithelial cell differentiation, proliferation, and apoptosis, lending weight to clinical evidence linking vitamin D 3 insufficiency to breast cancer incidence and mortality. Local dysregulation of vitamin D 3 metabolism has been identified in patients with breast cancer, implying that disruption of 1,25(OH) 2 D signaling may contribute to breast cancer development in an autocrine or paracrine manner. Mouse mammary glands express the critical enzymes responsible for 1,25(OH) 2 D synthesis (Cyp2r1 and Cyp27b1), degradation (Cyp24a1), as well as the vitamin D 3 receptor (Vdr), and genetically modified mouse models have revealed a great deal about the role of vitamin D 3 in cancer initiation and progression. Ablation of Vdr or Cyp27b1 in murine models of mammary cancer reduces the anti-tumor effects of vitamin D 3 , while elevation of Cyp24a1 levels increases degradation of 1,25(OH) 2 D, leading to diminished anti-tumor effects. This review discusses the recent transgenic mouse models of vitamin D 3 metabolism and the Vdr signaling network, and how these contribute to mammary gland development, and cancer tumorigenesis and progression. Collectively, these mouse models have helped clarify mechanisms of action of vitamin D 3 signaling and suggest that activation or restoration of the vitamin D 3 regulated pathway is a potential approach for human breast cancer prevention.