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.