Abstract
CD44 is a multifunctional transmembrane protein involved in cell proliferation, angiogenesis, invasion, and metastasis. CD44 is identified as a cancer stem cell marker, and the CD44-positive breast cancer cells are enriched in residual breast cancer cell populations after conventional therapies, suggesting that CD44 may be an important target for cancer prevention and therapy. Therefore, we investigated for the inhibitory effect of a novel Gemini vitamin D analog, 1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124), on mammary tumor growth and CD44 expression in MCF10DCIS.com human breast cancer in vitro and in vivo. MCF10DCIS.com cells were injected into mammary fat pads in immunodeficient mice, and BXL0124 was then administered intraperitoneally (0.1 μg/kg body weight) or orally (0.03 or 0.1 μg/kg body weight) 6 days a week for 5 weeks. At necropsy, mammary tumors and blood were collected for evaluating tumor growth, CD44 expression, and serum calcium level. BXL0124 suppressed mammary tumor growth and markedly decreased the expression of CD44 protein in MCF10DCIS xenograft tumors without causing hypercalcemic toxicity. BXL0124 also inhibited the expression of CD44 protein and mRNA as well as the transcriptional activity of the CD44 promoter in cultured MCF10DCIS.com cells. The repression of CD44 expression induced by BXL0124 was blocked by siRNA vitamin D receptor (VDR), indicating that the regulation of CD44 expression by BXL0124 is a VDR-dependent event. The novel Gemini vitamin D analog, BXL0124, represses CD44 expression in MCF10DCIS.com cells in vitro and in xenograft tumors, suggesting an inhibitory role of a Gemini vitamin D derivative on breast cancer stem cells.
Footnotes
This work was supported in part by the National Institutes of Health National Cancer Institute [R01-CA127645]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES005022]; and the Trustees Research Fellowship Program at Rutgers, the State University of New Jersey.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.068403.
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ABBREVIATIONS:
- 1α,25(OH)2D3
- 1α,25-dihydroxyvitamin D3
- BXL0124
- 1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol
- CD44s
- CD44 standard isoform
- CD44v
- CD44 variant isoform
- CD44v3
- CD44 containing variant domain 3
- CD44v6
- CD44 containing variant domain 6
- DAPI
- 4,6-diamidino-2-phenylindole
- DCIS
- ductal carcinoma in situ
- DMEM
- Dulbecco's modified Eagle's medium
- DMSO
- dimethyl sulfoxide
- H&E
- hematoxylin and eosin
- PCNA
- proliferating cell nuclear antigen
- qPCR
- quantitative polymerase chain reaction
- SCID
- severe combined immunodeficiency
- siRNA
- small interfering RNA
- VDR
- vitamin D receptor.
- Received August 25, 2010.
- Accepted November 16, 2010.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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