A novel gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer

Jae Young So, Hong Jin Lee, Amanda K. Smolarek, Shiby Paul, Chung Xiou Wang, Hubert Maehr, Milan Uskokovic, Xi Zheng, Allan H. Conney, Li Cai, Fang Liu, Nanjoo Suh

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)360-367
Number of pages8
JournalMolecular Pharmacology
Volume79
Issue number3
DOIs
StatePublished - Mar 1 2011

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Vitamin D
Stem Cells
Breast Neoplasms
Calcitriol Receptors
Neoplastic Stem Cells
Heterografts
Neoplasms
Growth
Body Weight
Proteins
Cholecalciferol
Residual Neoplasm
1,25-dihydroxy-21-(3-hydroxy-3-methyl-4,4,4-tributyl)-23-yne-26,27-hexafluorocholecalciferol
Small Interfering RNA
Adipose Tissue
Breast
Cell Proliferation
Neoplasm Metastasis
Calcium
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

So, Jae Young ; Lee, Hong Jin ; Smolarek, Amanda K. ; Paul, Shiby ; Wang, Chung Xiou ; Maehr, Hubert ; Uskokovic, Milan ; Zheng, Xi ; Conney, Allan H. ; Cai, Li ; Liu, Fang ; Suh, Nanjoo. / A novel gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer. In: Molecular Pharmacology. 2011 ; Vol. 79, No. 3. pp. 360-367.
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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.",
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A novel gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer. / So, Jae Young; Lee, Hong Jin; Smolarek, Amanda K.; Paul, Shiby; Wang, Chung Xiou; Maehr, Hubert; Uskokovic, Milan; Zheng, Xi; Conney, Allan H.; Cai, Li; Liu, Fang; Suh, Nanjoo.

In: Molecular Pharmacology, Vol. 79, No. 3, 01.03.2011, p. 360-367.

Research output: Contribution to journalArticle

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T1 - A novel gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer

AU - So, Jae Young

AU - Lee, Hong Jin

AU - Smolarek, Amanda K.

AU - Paul, Shiby

AU - Wang, Chung Xiou

AU - Maehr, Hubert

AU - Uskokovic, Milan

AU - Zheng, Xi

AU - Conney, Allan H.

AU - Cai, Li

AU - Liu, Fang

AU - Suh, Nanjoo

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