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- Title
The anti-proliferative effects of 1α,25(OH)<sub>2</sub>D<sub>3</sub> on breast and prostate cancer cells are associated with induction of BRCA1 gene expression.
- Authors
Campbell, Moray J; Gombart, Adrian F; Kwok, Scott H; Park, Susan; Koeffler, H Phillip
- Abstract
The anti-proliferative action of the seco-steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] extends to some, but not all breast and prostate cancer cell lines. By elucidating the molecular mechanisms mediating the sensitivity of these cells, we can identify critical target genes regulated directly or indirectly by 1α,25(OH)2D3 and pathways potentially disrupted during transformation. In this study, we demonstrated the induction of expression of BRCA1 mRNA and protein as well as transcriptional activation from the BRCA1-promoter by 1α,25(OH)2D3 in the sensitive breast cancer cell line MCF-7. This was not observed in the 1α,25(OH)2D3-resistant breast cancer cell line MDA-MB-436. The induction of BRCA1 mRNA was blocked by cyclohexamide. This indicated that transcriptional activation was mediated indirectly by the vitamin D receptor (VDR). Inhibition of VDR protein levels by stable transformation of the anti-sense VDR in MCF-7 reduced the sensitivity of MCF-7 to 1α,25(OH)2D3 by 50-fold. In addition, the induction of BRCA1 protein and transcriptional activation of a BRCA1 promoter-luciferase reporter construct was abrogated in the stable transformant with the greatest reduction of VDR levels. Examination of other breast and prostate cancer cell lines revealed that sensitivity to the anti-proliferative effects of 1α,25(OH)2D3 was strongly associated with an ability to modulate BRCA1 protein. Furthermore, the expression of the estrogen receptor in these cell lines strongly correlated with their sensitivity to 1α,25(OH)2D3 and their ability to modulate BRCA1 expression. Taken together, our data support a model whereby the anti-proliferative effects of 1α,25(OH)2D3 are mediated, in part, by the induction of BRCA1 gene expression via...
- Subjects
STEROID hormones; CANCER cells; CELL lines; GENES; BREAST cancer
- Publication
Oncogene, 2000, Vol 19, Issue 44, p5091
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1203888