The role of vitamin D in breast cancer risk and progression

The active form of vitamin D-3, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), is primarily known as a key regulator of calcium and phosphate homeostasis. It exerts its biological functions by binding to the vitamin D receptor (VDR), a transcription factor that regulates gene expression in vitamin D-target tissues such as intestine, kidney and bone. Yet, the VDR is expressed in many additional normal and cancerous tissues, where it moderates the antiproliferative, prodifferentiating and immune-modulating effects of 1,25(OH)(2)D-3. Interestingly, several epidemiological studies show that low levels of 25(OH)D, a biological marker for 1,25(OH)(2)D-3 status, are associated with an increased risk of breast cancer (BC) development. Mendelian randomization studies, however, did not find any relationship between single-nucleotide polymorphisms in genes associated with lower serum 25(OH)D and BC risk. Nevertheless, multiple and in vivo preclinical studies illustrate that 1,25(OH)(2)D-3 or its less calcaemic structural analogues influence diverse cellular processes in BC such as proliferation, differentiation, apoptosis, autophagy and the epithelial-mesenchymal transition. Recent insights also demonstrate that 1,25(OH)(2)D-3 treatment impacts on cell metabolism and on the cancer stem cell population. The presence of VDR in the majority of BCs, together with the various anti-tumoural effects of 1,25(OH)(2)D-3, has supported the evaluation of the effects of vitamin D-3 supplementation on BC development. However, most randomized controlled clinical trials do not demonstrate a clear decrease in BC incidence with vitamin D-3 supplementation. However, 1,25(OH)(2)D-3 or its analogues seem biologically more active and may have more potential anticancer activity in BC upon combination with existing cancer therapies.

Automated summary

The active form of vitamin D-3, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), plays a key role in regulating calcium and phosphate levels. Low levels of 25(OH)D, a marker for 1,25(OH)(2)D-3, are associated with an increased risk of breast cancer (BC) development. However, vitamin D-3 supplementation does not show a significant decrease in BC incidence. 1,25(OH)(2)D-3 or its analogues may have more potential anticancer activity when combined with existing cancer therapies.