Autocrine metabolism of vitamin D in normal and malignant breast tissue

Purpose: Vitamin D seems to exert a protective effect against common cancers, although this does not correlate with circulating levels of active 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], indicating a more localized activation of vitamin D. The aim of this study was to investigate the significance of this in breast cancer. Experimental Design: Quantitative reverse transcription-PCR analysis of mRNA expression was carried out for the vitamin D-activating enzyme 1 alpha-hydroxylase, the catabolic enzyme 24-hydroxylase, and the vitamin D receptor in 41 tumors and paired nonneoplastic tissue as well as breast cancer cell lines. Immunohistochemistry was used to assess 1 alpha-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism. Results: Expression of mRNA for 1 alpha-hydroxylase (27-fold; P <5 x 10(-11)), vitamin D receptor (7-fold; P <1.5 x 10(-8)), and 24-hydroxylase (4-fold; P <0.02) was higher in breast tumors. 1 alpha-Hydroxylase enzyme activity was also higher in tumors (44.3 +/- 11.4 versus 12.4 +/- 4.8 fmol/h/mg protein in nonneoplastic tissue; P <0.05). However, production of inactive 1,24,25-trihydroxy-vitamin D-3 was also significantly higher in tumors (84.8 +/- 11.7 versus 33.6 +/- 8.5 fmol/h/mg protein; P <0.01). Antisense inhibition of 24-hydroxylase in vitro increased antiproliferative responses to 1,25(OH)(2)D-3. Conclusion: These data indicate that the vitamin D-activating enzyme 1 alpha-hydroxylase is upregulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH)(2)D-3 production in tumors by catalyzing catabolism to less active vitamin D metabolites. The enzymes involved in autocrine metabolism of vitamin D in breast tissue may therefore provide important targets for both the prevention and treatment of breast cancer.