25-hydroxy-D3 as a possible chemopreventive agent for breast cancer

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DESCRIPTION (provided by applicant): 1,25(OH)2 D3 is the active metabolite of vitamin D action and serves as a ligand for vitamin D receptors. Although at a physiological concentration, it may not be toxic, it also does not have any chemopreventive activity at this level. At higher concentrations it is highly calcemic. With recent discovery that 1a(OH)ase (CYP27B1) is expressed in multiple vitamin D target tissues, it is possible that 25(OH)D3 can be used as a major natural protective agent in serum. It can be converted to the active 1,25(OH)2D3 in the cells by CYP27B1, allowing its function in cell growth modulation and differentiation. In this study, we will test the hypothesis that the 25(OH)D3 maintains the cell differentiation and inhibits transformation by conversion to 1,25(OH)2D3 in normal breast epithelial cells expressing CYP27B1. The long term goal is to develop 25(OH)D3 as a natural chemopreventive agent for breast cancer. Since the key for the conversion of 25(OH)D3 to active 1,25(OH)2D3 is vitamin D metabolizing enzyme CYP27B1 in breast epithelial cells, we have designed two specific aims to systematically address this issue in this project: Aim 1. To demonstrate the expression and regulation of CYP27B1 in both normal breast and breast cancer epithelial. For this aim, we ask three questions: 1. Is there any difference in expression of CYP27B1 between normal and tumor breast epithelial cells at transcriptional and translational levels? 2. Is CYP27B1 expression and regulation related to cell differentiation? 3. Is transcription (or promoter regulation) of CYP27B1 tissue specific? If transcription is tissue specific, is there any potential use of 25(OH)D3 for breast cancer chemoprevention and therapy? Aim 2. To determine the functional role of 25(OH)D3 in breast cancer chemoprevention. For this aim, we ask three questions: 1. Does 25(OH)D3 inhibit cell proliferation or induce differentiation in breast epithelial cells? 2. Does 25(OH)D3 inhibit the mammary alveolar lesion formation induced by DMBA and whether this effect is selective during the initiation or promotion phases of lesion formation? 3. Does 25(OH)D3 protect normal breast epithelial cells against transformation induced by carcinogen treatment? Results generated from this study will establish the role of 25(OH)D3 in breast cancer chemoprevention and form the basis of a more extensive RO1 application.