Vitamin D3 suppresses the androgen-stimulated growth of mouse mammary carcinoma SC-3 cells by transcriptional repression of fibroblast growth factor 8
✍ Scribed by Hirotoshi Kawata; Tomoko Kamiakito; Norio Takayashiki; Akira Tanaka
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 199 KB
- Volume
- 207
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Active metabolites of vitamin A and D are well known to act as growth inhibitors in hormone‐related prostate and breast cancers. When various concentrations of 1α,25‐dihydroxyvitamin D3 (vitamin D3), all‐trans‐retinoic acid (ATRA) and 9‐cis retinoic acid (9‐cis RA) were examined, the androgen‐stimulated growth of mouse mammary carcinoma SC‐3 cells was inhibited by vitamin D3 alone in a dose‐dependent manner. A flow cytometer analysis showed that vitamin D3 leads SC‐3 cells to relative G1‐growth arrest after 72 h. Characterization of vitamin D3‐responsive genes using an oligonucleotide microarray demonstrated that 220 genes were upregulated at more than threefold, and 84 genes were downregulated to less than one‐third, compared with the testosterone‐stimulated SC‐3 cells. Neither cyclin‐dependent kinase inhibitors (CDKIs) nor the antiapoptotic bcl‐2 gene were induced in vitamin D3‐responsive genes, with the exception of a slight induction of p15^INK4B^. Importantly, fgf8 was markedly repressed in response to vitamin D3. The exogenous addition of FGF8 canceled the growth suppression by vitamin D3 in SC‐3 cells, suggesting that the repression of fgf8 is an indispensable step in vitamin D3‐mediated growth inhibition. In reporter assays using the ARE‐containing artificial construct and the natural androgen‐regulated PSA promoter, co‐transfection of the vitamin D receptor (VDR) and androgen receptor (AR) suppressed AR‐stimulated promoter activity. In addition, vitamin D3 also suppressed androgen‐stimulated promoter activity in the stably transfected SC‐3 cells. Moreover, VDR repressed the core promoter activity of fgf8 in COS1 cells and in the SC‐3 cells. All these findings strongly suggest that vitamin D3 serves as a negative regulator for both androgen‐related and fgf8 transcriptions. J. Cell. Physiol. © 2006 Wiley‐Liss, Inc.