Identification and characterization of cancer stem cells in cancer development offers a new promising strategy in cancer prevention. Targeting cancer stem cells by novel cancer preventive agents may provide a new approach to blocking the progression of premalignant tumors into invasive cancer. CD44, a transmembrane glycoprotein, is a major receptor for extracellular proteins involved in invasion and metastasis of human cancers. CD44 has been recognized as one of the key cell surface markers for tumor-initiating cells in breast cancer. Our laboratory has demonstrated that the novel Gemini vitamin D analog BXL0124 [1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluro-cholecalciferol] represses CD44 expression in basal-like human breast cancer cells and inhibits MCF10DCIS xenograft tumor growth. We have investigated potential factors downstream of CD44 and the biological role of CD44 repression by BXL0124 in MCF10DCIS cells. CD44 forms a complex with STAT3 and Janus kinase 2 (JAK2) to activate STAT3 signaling, which was inhibited by BXL0124 in MCF10DCIS cells. The knockdown of CD44 by small hairpin RNA significantly decreased mRNA expression levels of invasion markers in MCF10DCIS cells and decreased tumor size and weight as well as invasion markers in MCF10DCIS xenograft tumors. Repression of CD44-STAT3 signaling by the Gemini vitamin D analog BXL0124 appears to be a key molecular mechanism in the inhibition of breast cancer invasion. Identification of new targets and pathways in specific populations of cancer stem cells, such as those expressing CD44, may open a new direction in cancer prevention research. (Supported by NIH grant R01 CA127645).

Citation Format: Nanjoo Suh. Novel Gemini vitamin D compounds for prevention of breast cancer by targeting stem cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN08-04.