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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA121365-02
Application #
7213255
Study Section
Special Emphasis Panel (ZCA1-SRRB-Q (J1))
Program Officer
Davis, Cindy D
Project Start
2006-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$91,634
Indirect Cost
Name
Iit Research Institute
Department
Type
DUNS #
005447826
City
Chicago
State
IL
Country
United States
Zip Code
60616
Alimirah, Fatouma; Peng, Xinjian; Yuan, Liang et al. (2012) Crosstalk between the peroxisome proliferator-activated receptor ? (PPAR?) and the vitamin D receptor (VDR) in human breast cancer cells: PPAR? binds to VDR and inhibits 1?,25-dihydroxyvitamin D3 mediated transactivation. Exp Cell Res 318:2490-7
Alimirah, Fatouma; Vaishnav, Avani; McCormick, Michael et al. (2010) Functionality of unliganded VDR in breast cancer cells: repressive action on CYP24 basal transcription. Mol Cell Biochem 342:143-50
Peng, Xinjian; Vaishnav, Avani; Murillo, Genoveva et al. (2010) Protection against cellular stress by 25-hydroxyvitamin D3 in breast epithelial cells. J Cell Biochem 110:1324-33
Peng, Xinjian; Hawthorne, Michael; Vaishnav, Avani et al. (2009) 25-Hydroxyvitamin D3 is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture. Breast Cancer Res Treat 113:31-41
Peng, Xinjian; Jhaveri, Pavan; Hussain-Hakimjee, Erum A et al. (2007) Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1alpha-hydroxyvitamin D5. Carcinogenesis 28:1000-7