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Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue

Authors' Affiliations: ¹ Division of Medical Sciences, Institute of Biomedical Research, Endocrinology and Metabolism, University of Birmingham, Birmingham, United Kingdom and ² Department of Cellular and Molecular Medicine, St. George's Hospital Medical School, London, United Kingdom

Requests for reprints: Martin Hewison, Division of Medical Sciences, Institute of Biomedical Research, Endocrinology and Metabolism, University of Birmingham, Birmingham B15 2TT, United Kingdom. Phone: 44-121-414-3776; Fax: 44-121-415-8712; E-mail: M.Hewison{at}bham.ac.uk.

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 D₃ [1,25(OH)₂D₃], 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-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-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism.

Results: Expression of mRNA for 1-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-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-trihydroxyvitamin D₃ 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)₂D₃.

Conclusion: These data indicate that the vitamin D–activating enzyme 1-hydroxylase is up-regulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH)₂D₃ 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.

Key Words: vitamin D • breast cancer • 1-hydroxylase • 24-hydroxylase • vitamin D receptor

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