Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer

• Published in: Biochemical pharmacology 2006-07, Vol.72 (3), p.332-343
• Main Authors: Lee, Hong Jin, Liu, Hao, Goodman, Catherine, Ji, Yan, Maehr, Hubert, Uskokovic, Milan, Notterman, Daniel, Reiss, Michael, Suh, Nanjoo
• Format: Article
• Language: English
• Subjects: Apoptosis - genetics; Biological and medical sciences; Blotting, Western; Bone morphogenetic protein; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Calcitriol - analogs & derivatives; Calcitriol - chemistry; Calcitriol - pharmacology; Cell Adhesion - genetics; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Gemini Vitamin D 3; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; MCF10; Medical sciences; Molecular Structure; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Smad3; Structure-Activity Relationship; TGF-β; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Tumors; Up-Regulation - drug effects
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2006.04.030

We investigated gene expression changes induced by a novel Gemini Vitamin D 3 analog, RO-438-3582 (1α,25-dihydroxy-20 S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluoro-cholecalciferol, Ro3582), in a unique human breast MCF10 model. We used two breast epithelial cell lines from this model, namely MCF10AT1 ( Ha-ras oncogene transfected MCF10A, early premalignant) and MCF10CA1a (fully malignant and metastatic derived from the MCF10AT1 line). We analyzed gene expression changes induced by Ro3582 using GeneChip technology, quantitative RT-PCR, Western blot analysis, or a gene transcription assay. Interestingly, we found distinct gene expression profile differences between Ro3582-induced response of the early premalignant MCF10AT1 and the malignant and metastatic MCF10CA1a cell lines. Moreover, while the Gemini Vitamin D 3 analog Ro3582 modulated the expression of several Vitamin D target genes such as the 24-hydroxylase, CD14, osteocalcin, and osteopontin in both cell lines, Ro3582 regulated many genes involved in cell proliferation and apoptosis, cell adhesion, invasion, angiogenesis as well as cell signaling pathways, such as the BMP and TGF-β systems, differently in the two cell lines. The Gemini Vitamin D 3 analog Ro3582 induced more significant gene changes in the early premalignant MCF10AT1 cells than in the malignant metastatic MCF10CA1a cells, suggesting that Gemini Vitamin D 3 analogs may be more effective in preventing the progression of an early stage of breast carcinogenesis than in treating late stage breast cancer.