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A Novel Vitamin D Derivative Activates Bone Morphogenetic Protein Signaling in MCF10 Breast Epithelial Cells

Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey (H.J.L., A.W., C.G., Y.J., H.M., M.U., N.S.); and the Cancer Institute of New Jersey, New Brunswick, New Jersey (R.G., M.R.)

We investigated the action of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], a novel Gemini vitamin D₃ analog Ro-438-3582 [1,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluorocholecalciferol (Ro3582)], and a classic vitamin D₃ analog Ro-26-2198 [1,25-dihydroxy-16,23(Z)-diene-26,27-hexafluoro-19-nor-cholecalciferol (Ro2198)] in modulating the transforming growth factor- (TGF-)/bone morphogenetic protein (BMP) system in MCF10 immortalized breast epithelial cells. We found that 1,25(OH)₂D₃, Ro3582, and Ro2198 all enhanced BMP/Smad signaling by increasing the phosphorylation of receptor-regulated Smads. Ro3582 was more active than Ro2198, but both were considerably more active than 1,25(OH)₂D_3. Ro3582 enhanced BMP/Smad signaling by 1) inducing the phosphorylation of receptor-regulated Smads (Smad1/5), 2) increasing the accumulation of phosphorylated Smad1/5 in the nucleus, and 3) activating BMP-mediated transcription in MCF10 breast epithelial cells. Furthermore, Ro3582 induced the synthesis of BMP-2 and BMP-6 mRNA and protein, and the expression of Smad6 mRNA in MCF10 breast epithelial cells was inhibited by Ro3582. The induction of phospho-Smad1/5 by Ro3582 was inhibited by treatment with the BMP antagonist Noggin, whereas neutralizing antibody to TGF- did not block the induction of phospho-Smad1/5 by Ro3582. Treatment with Noggin also blocked the effect of Ro3582 on nuclear accumulation of phospho-Smad1/5 and the induction of BMP-2 and BMP-6 mRNA synthesis. These results indicate that the activation of BMP/Smad signaling by the Gemini vitamin D₃ analog Ro3582 may be through the production of BMP ligands, including BMP-2 and BMP-6, and/or down-regulation of the inhibitory Smad6. This is the first report to show that 1,25(OH)₂D₃ and its derivatives activate BMP/Smad-specific signaling in human breast epithelial cells.

Address correspondence to: Dr. N. Suh, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854. E-mail: nsuh{at}rci.rutgers.edu

This article has been cited by other articles:

				H. J. Lee, S. Paul, N. Atalla, P. E. Thomas, X. Lin, I. Yang, B. Buckley, G. Lu, X. Zheng, Y.-R. Lou, et al. Gemini Vitamin D Analogues Inhibit Estrogen Receptor-Positive and Estrogen Receptor-Negative Mammary Tumorigenesis without Hypercalcemic Toxicity Cancer Prevention Research, November 1, 2008; 1(6): 476 - 484. [Abstract] [Full Text] [PDF]

				H. J. Lee, Y. Ji, S. Paul, H. Maehr, M. Uskokovic, and N. Suh Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase C{alpha} Cancer Res., December 15, 2007; 67(24): 11840 - 11847. [Abstract] [Full Text] [PDF]