24R,25-dihydroxyvitamin D₃ modulates tumorigenicity in breast cancer in an estrogen receptor-dependent manner

Vitamin D has long been prescribed as a supplement to breast cancer patients. This is partially motivated by data indicating that low serum vitamin D, measured as 25-hydroxyvitamin D3 [25(OH)D₃], is associated with worsened cancer prognosis and decreased survival rates in cancer patients. However, clinical studies investigating the role of vitamin D supplementation in breast cancer treatment are largely inconclusive. One reason for this may be that many of these studies ignore the complexity of the vitamin D metabolome and the effects of these metabolites at the cellular level. Once ingested, vitamin D is metabolized into 37 different metabolites, including 25(OH)D₃, which is the metabolite actually measured clinically, as well as 1,25(OH)₂D₃ and 24,25(OH)₂D₃. Recent work by our lab and others has demonstrated a role for 24R,25(OH)₂D₃, in the modulation of breast cancer tumors via an estrogen receptor α-dependent mechanism. This review highlights the importance of considering estrogen receptor status in vitamin D-associated prognostic studies of breast cancer and proposes a potential mechanism for 24R,25(OH)₂D₃ signaling in breast cancer cells.