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01-01-2009 | Preclinical Study

25-Hydroxyvitamin D₃ is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture

Authors: Xinjian Peng, Michael Hawthorne, Avani Vaishnav, René St-Arnaud, Rajendra G. Mehta

Published in: Breast Cancer Research and Treatment | Issue 1/2009

Abstract

Despite the role of vitamin D₃ endocrine system in prevention of mammary gland transformation in animal models, use of 1,25(OH)₂D₃in clinical settings is precluded due to its toxicity in vivo. Therefore much effort has been placed in developing relatively non-toxic vitamin D analogs. Recently, with the discovery of the expression of 25-hydroxy vitamin D₃ 1α-hydroxylase (CYP27B1) in multiple extrarenal organs, the functional role of prohormone, 25-hydroxyvitamin D₃ [25(OH)D₃], has been redefined. Since 25(OH)D₃ does not cause hypercalcemia and maintains relative high concentration in serum, it is possible that the prohormone can be converted to active hormone in mammary epithelial cells to provide chemopreventive effects. In the present study, we evaluated its functional significance using mouse mammary organ culture (MMOC) system. We first showed that 25(OH)D₃ 1α-hydroxylase is extensively expressed in mammary ductal epithelial cells at both protein and mRNA levels, which is a prerequisite for 25(OH)D₃ to function in an autocrine/paracrine manner. However, we also observed that clotrimazol (1α-hydroxylase inhibitor) enhanced 25(OH)D₃ -induced CYP24 expression in breast cancer cells. In mammary glands derived from 1α-hydroxylase knockout mice, 25(OH)D₃ treatment in organ culture significantly induced CYP24 expression, indicating a potential direct effect of 25(OH)D₃. In MMOC, 100–250 nM 25(OH)D₃ suppressed both ovarian hormone-dependent and -independent mammary precancerous lesions (induced by DMBA) by more than 50%, while the active hormone 1,25(OH)₂D₃ (positive control) at 100 nM suppressed alveolar lesions by more than 80%. The inactive vitamin D₃ (negative control) at 100 nM suppressed alveolar lesions by only 20% (P > 0.05). We found that 25(OH)D₃ inhibits DMBA-induced mammary alveolar lesions (MAL) in a stage-specific manner: 25(OH)D₃ mainly inhibits the promotion stage of lesion formation. We conclude that 25(OH)D₃ could serve as a non-toxic natural chemopreventive agent for further development for breast cancer prevention.

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Title: 25-Hydroxyvitamin D3 is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture
Authors: Xinjian Peng
Michael Hawthorne
Avani Vaishnav
René St-Arnaud
Rajendra G. Mehta
Publication date: 01-01-2009
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-008-9900-0

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