The role of vitamin D in reducing cancer risk and progression

Vitamin D3 is the precursor to the potent steroid hormone calcitriol (1,25 dihydroxyvitamin D3 (1,25(OH)2D3)) that regulates the expression of many genes in most tissues of the body.Dietary vitamin D3 is converted into 25 hydroxyvitamin D3 (25(OH)D3) in the liver; this is the circulating form of vitamin D, which is subsequently hydroxylated to form calcitriol by the cytochrome P450 enzyme CYP27B1 in the kidneys. Calcitriol is also synthesized locally by CYP27B1 present in most extrarenal tissues, including many cancer cells, where it acts in a paracrine manner. Levels of calcitriol are additionally regulated by the cytochrome P450 enzyme CYP24A1, which begins the inactivation of calcitriol through 24-hydroxylation.Calcitriol regulates multiple signalling pathways involved in proliferation, apoptosis, differentiation, inflammation, invasion, angiogenesis and metastasis, and it therefore has the potential to affect cancer development and growth. Recent findings indicate that calcitriol also regulates microRNA expression and may affect cancer stem cell biology.Multiple cell culture and animal models of cancer support a role for dietary vitamin D3 and calcitriol in retarding cancer development and progression; however, data from human clinical trials are thus far inconsistent.Epidemiological studies suggest that vitamin D deficiency is associated with increased incidence of cancer and worse outcomes, although many studies do not demonstrate these associations.Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and vitamin D3 synthesis and degradation pathways have been implicated in affecting the risk of cancer development.Given the interest in using vitamin D3 to reduce cancer risk, further research is needed, particularly randomized controlled trials (RCTs), to demonstrate in humans whether individuals with low levels of circulating 25(OH)D are at increased risk of developing cancer and whether calcitriol or vitamin D supplements can reduce cancer risk and progression and improve outcomes.