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    Contents lists available at ScienceDirect
    journal homepage:
    24R,25-dihydroxyvitamin D3 modulates tumorigenicity in breast cancer in T an AS1517499 receptor-dependent manner
    Anjali Vermaa, Zvi Schwartza,b, Barbara D. Boyana,c,
    a Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, United States
    b Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78249, United States
    c Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States
    Keywords: 24R,25-dihydroxyvitamin D3 Estrogen receptor α Breast cancer
    Vitamin D
    Phospholipase D 
    Vitamin D has long been prescribed as a supplement to breast cancer patients. This is partially motivated by data indicating that low serum vitamin D, measured as 25-hydroxyvitamin D3 [25(OH)D3], is associated with wor-sened cancer prognosis and decreased survival rates in cancer patients. However, clinical studies investigating the role of vitamin D supplementation in breast cancer treatment are largely inconclusive. One reason for this may be that many of these studies ignore the complexity of the vitamin D metabolome and the effects of these metabolites at the cellular level. Once ingested, vitamin D is metabolized into 37 different metabolites, including 25(OH)D3, which is the metabolite actually measured clinically, as well as 1,25(OH)2D3 and 24,25(OH)2D3. Recent work by our lab and others has demonstrated a role for 24R,25(OH)2D3, in the modulation of breast cancer tumors via an estrogen receptor α-dependent mechanism. This review highlights the importance of considering estrogen receptor status in vitamin D-associated prognostic studies of breast cancer and proposes a potential mechanism for 24R,25(OH)2D3 signaling in breast cancer cells.
    1. Introduction
    Several ecological and meta-analytical studies have reported a link between breast cancer prognosis and sun exposure, prompting clin-icians to investigate the role of vitamin D in breast cancer prognosis. Of the over 250,000 women who are diagnosed with breast cancer every year [1], over half are believed to supplement their diet with some form of vitamin D [2]. The majority of studies that investigate vitamin D and breast cancer have focused on serum levels of the vitamin D metabolite, 25-hydroxyvitamin D3 [25(OH)D3], and their correlation with breast cancer prognosis. While meta-analyses and some clinical studies have demonstrated a relationship between low serum 25(OH)D3 and in-creased breast cancer incidence and mortality, the majority of clinical trials evaluating the efficacy of vitamin D supplementation on breast cancer progression have been inconclusive [3–7]. Two major reasons for this lack of consensus may be that most vitamin-D studies ignore the hormone receptor profiles of enrolled patients’ breast cancers, and that “serum vitamin D”, which is measured clinically as 25(OH)D3, is an incomplete portrait of the relative production of vitamin D metabolites such as 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], 24R,25-dihy-droxyvitamin D3 [24R,25(OH)2D3], and 1α,24R,25-trihydroxyvitamin D3 [1,24,25(OH)3D3] and their subsequent effects on cancer prognoses.