Aromatase, the enzyme that catalyzes estrogen synthesis, is critical for the progression of estrogen receptor-positive breast cancer (BCa) in postmenopausal women. We show that calcitriol, the hormonally active form of vitamin D, regulates the expression of aromatase in a tissue-selective manner. Calcitriol significantly decreased aromatase expression in human BCa cells and adipocytes and caused substantial increases in human osteosarcoma cells (a bone cell model exhibiting osteoblast phenotype in culture) and modest increases in ovarian cancer cells. Calcitriol administration to immunocompromised mice bearing human BCa xenografts decreased aromatase mRNA levels in the tumors and the surrounding mammary adipose tissue but did not alter ovarian aromatase expression. In BCa cells, calcitriol also reduced the levels of prostaglandins (PGs), major stimulators of aromatase transcription, by suppressing the expression of cyclooxygenase-2 (which catalyzes PG synthesis) and increasing that of 15-hydroxyprostaglandin dehydrogenase (which catalyzes PG degradation). The mechanism of aromatase down-regulation by calcitriol in BCa cells is therefore 2-fold: a direct repression of aromatase transcription via promoter II through the vitamin D-response elements identified in this promoter and an indirect suppression by reducing the levels of PGs. Combinations of calcitriol with three different aromatase inhibitors (AIs) caused enhanced inhibition of BCa cell growth. The combination of calcitriol and an AI may have potential benefits for BCa therapy. In addition to augmenting the ability of AIs to inhibit BCa growth, calcitriol acting as a selective aromatase modulator that increases aromatase expression in bone would reduce the estrogen deprivation in bone caused by the AIs, thus ameliorating the AI-induced side effect of osteoporosis.

1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃ or calcitriol], the hormonally active vitamin D metabolite, exhibits anticancer actions in models of breast cancer and prostate cancer. Because CYP27B1 (1α-hydroxylase), the enzyme catalyzing 1,25(OH)₂D₃ formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D₃ will be converted to 25(OH)D₃ in the body and then to 1,25(OH)₂D₃ locally in the cancer microenvironment in which it will exert autocrine/paracrine anticancer actions. Immunocompromised mice bearing MCF-7 breast cancer xenografts showed significant tumor shrinkage (>50%) after ingestion of a vitamin D₃-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg). Dietary vitamin D₃ inhibition of tumor growth was equivalent to administered calcitriol (0.025, 0.05, or 0.1 μg/mouse, three times a week). Both treatments equivalently inhibited PC-3 prostate cancer xenograft growth but to a lesser extent than the MCF-7 tumors. Calcitriol at 0.05 μg and 0.1 μg caused modest but statistically significant increases in serum calcium levels indicating that the dietary vitamin D₃ comparison was to a maximally safe calcitriol dose. Dietary vitamin D₃ did not increase serum calcium, demonstrating its safety at the concentration tested. The vitamin D₃ diet raised circulating 1,25 dihydroxyvitamin D levels and did not alter CYP27B1 mRNA in the kidney but increased it in the tumors, suggesting that extrarenal sources including the tumors contributed to the elevated circulating 1,25 dihydroxyvitamin D₃. Both calcitriol and dietary vitamin D₃ were equipotent in suppressing estrogen synthesis and signaling and other proinflammatory and growth signaling pathways. These preclinical data demonstrate the potential utility of dietary vitamin D₃ supplementation in cancer prevention and therapy.

Heterogeneous loss of function mutations in the vitamin D receptor (VDR) interfere with vitamin D signaling and cause hereditary vitamin D-resistant rickets (HVDRR). HVDRR is characterized by hypocalcemia, secondary hyperparathyroidism and severe early-onset rickets in infancy and is often associated with consanguinity. Affected children may also exhibit alopecia of the scalp and total body. The children usually fail to respond to treatment with calcitriol; in fact, their endogenous levels are often very elevated. Successful treatment requires reversal of hypocalcemia and secondary hyperparathyroidism and is usually accomplished by administration of high doses of calcium given either intravenously or sometimes orally to bypass the intestinal defect in VDR signaling.