Gemini vitamin D analog suppresses ErbB2-positive mammary tumor growth via inhibition of ErbB2/AKT/ERK signaling.

Abstract

Numerous synthetic vitamin D analogs have been studied for their effects on the prevention and treatment of breast cancer. However, the inhibitory effects of naturally occurring 1alpha,25-dihydroxyvitamin D3 or its synthetic analogs on ErbB2 overexpressing mammary tumorigenesis have not been reported. Gemini vitamin D analogs are novel synthetic vitamin D derivatives with a unique structure of two six-carbon chains at C-20. We have previously shown that Gemini vitamin D analogs significantly inhibited carcinogen-induced estrogen receptor (ER)-positive mammary tumorigenesis and reduced ER-negative MCF10DCIS.com xenograft tumor growth without hypercalcemic toxicity. In the present study, we have determined the inhibitory effect of a potent Gemini vitamin D analog BXL0124 (1alpha,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol) on the ErbB2/Her-2/neu overexpressing mammary tumorigenesis. The Gemini BXL0124 inhibits ErbB2-positive mammary tumor growth and down-regulates the phosphorylation of ErbB2, ERK and AKT in tumors of MMTV-ErbB2/neu transgenic mice. These effects of Gemini BXL0124 in vivo were confirmed by using the ErbB2 overexpressing tumor cells derived from the mammary tumors of MMTV-ErbB2/neu mice. In conclusion, the Gemini vitamin D analog BXL0124 inhibits the growth of ErbB2 overexpressing mammary tumors through regulating the ErbB2/AKT/ERK signaling pathways, suggesting that Gemini vitamin D analog may be considered for translational studies.

• Authors: Hong Jin Lee, Jae-Young So, Andrew DeCastro, Amanda Smolarek, Shiby Paul, Hubert Maehr, Milan Uskokovic, Nanjoo Suh
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 121 Issue 1-2 Pg. 408-12 (Jul 2010) ISSN: 1879-1220 [Electronic] England
• PMID: 20304052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• 1,25-dihydroxy-21-(3-hydroxy-3-methyl-4,4,4-tributyl)-23-yne-26,27-hexafluorocholecalciferol
• 1,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3)
• Carcinogens
• Cholecalciferol
• Erbb2 protein, mouse
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 3
• Calcitriol
• Calcium

Topics

• Animals
• Calcitriol (analogs & derivatives, pharmacology)
• Calcium (metabolism)
• Carcinogens
• Cell Line, Tumor
• Cell Proliferation
• Cholecalciferol (analogs & derivatives)
• Mammary Neoplasms, Animal (metabolism)
• Mice
• Mice, Transgenic
• Microscopy, Fluorescence (methods)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, ErbB-2 (metabolism)
• Signal Transduction