Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 103–109 Biological actions of extra-renal 25-hydroxyvitamin D-1-hydroxylase and implications for chemoprevention and treatment Kelly Townsend a , Katie N. Evans a , Moray J. Campbell a , Kay W. Colston b , John S. Adams c , Martin Hewison a,∗ a Division of Medical Sciences, Institute of Biomedical Research, The University of Birmingham, Birmingham B15 2TH, UK b Department of Cellular and Molecular Medicine, St. George’s Hospital Medical School, London SW17 ORE, UK c Division of Endocrinology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA Abstract The Vitamin D-activating enzyme 25-hydroxyvitamin D-1-hydroxylase (1-hydroxylase) is now known to be expressed in a much wider range of tissues that previously thought, suggesting a role for 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), which is more in keeping with a cytokine than a hormone. In this capacity, the function of 1-hydroxylase in tumors is far from clear. Studies from several groups including ours have shown altered expression of 1-hydroxylase in different types of neoplasm including breast, prostate and colon cancers. However, functional analysis of Vitamin D metabolism in cancer is complicated by the heterogenous composition of tumors. Immunohistochemical analysis of breast tumors has shown that 1-hydroxylase is expressed by both epithelial cells and by tumor-infiltrating macrophages, suggesting an immunomodulatory component to 1,25(OH) 2 D 3 production in some types of cancer. The demonstration of 1-hydroxylase activity in tumors and their equivalent normal tissues has implications for both the treatment and prevention of cancers. For example, in tumors chemotherapy options may include the use of non-1-hydroxylated Vitamin D analogs to increase local concentrations of active metabolites without systemic side-effects. The role of 1-hydroxylase in protection against cancer is likely to be more complicated and may involve anti-tumor immune responses. © 2005 Elsevier Ltd. All rights reserved. Keywords: 25-Hydroxyvitamin D-1-hydroxylase; Tumors; Cancer 1. Introduction The active form of Vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), is a pluripotent seco-steroid with puta- tive applications that extend far beyond its classical role as a regulator of calcium homeostasis. In particular, the anti-proliferative and immunomodulatory properties of 1,25(OH) 2 D 3 have promoted its use as therapy for autoim- mune disease [1–3], transplantation rejection [1,3,4] and proliferative disorders such as psoriasis [5]. However, it is the possible use of 1,25(OH) 2 D 3 as an anti-cancer agent that has attracted most attention [6]. Studies in vitro have shown that 1,25(OH) 2 D 3 is able to block cell-cycle pro- gression and influence apoptosis in tumor cells, although translation of these effects in vivo has been compromised by ∗ Corresponding author. Tel.: +44 121 414 3776; fax: +44 121 415 8712. E-mail address: M.Hewison@bham.ac.uk (M. Hewison). significant hypercalcemic side-effects [7]. As a consequence there has been a concerted effort to improve the specificity of 1,25(OH) 2 D 3 therapy through the generation of synthetic analogs or deltanoids that retain the anti-proliferative prop- erties of the hormone while minimising calciotropic side- effects [3]. A more rational approach to this strategy has been facilitated by recent studies which have recognized that 1,25(OH) 2 D 3 signaling via nuclear Vitamin D recep- tors (VDR) is likely to be subject to gene and tissue-specific ‘tuning’ by virtue of their interaction with accessory proteins [8]. Strategies to improve the therapeutic index of 1,25(OH) 2 D 3 and its analogs remain a cornerstone of Vitamin D research. However, while most of this work has focused on the treatment of cancer, there is now increasing awareness of the potential role of 1,25(OH) 2 D 3 in tumor prevention. This has stemmed in part from studies of the impact of Vitamin D intake and status on cancer risk and 0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.06.004