The anti-proliferative effects of 1alpha,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression.
The anti-proliferative action of the seco-steroid hormone 1alpha, 25-dihydroxyvitamin D3 [1alpha,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 1alpha,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 1alpha,25(OH)2D3 in the sensitive breast cancer cell line MCF-7. This was not observed in the 1alpha,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 1alpha,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 1alpha, 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 1alpha,25(OH)2D3 and their ability to modulate BRCA1 expression. Taken together, our data support a model whereby the anti-proliferative effects of 1alpha,25(OH)2D3 are mediated, in part, by the induction of BRCA1 gene expression via transcriptional activation by factors induced by the VDR and that this pathway is disrupted during the development of prostate and breast cancers.
Campbell
M J
MJ
Department of Medicine, Division of Medical Sciences, University of Birmingham, Clinical Research Institute, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK.
Gombart
A F
AF
Kwok
S H
SH
Park
S
S
Koeffler
H P
HP
D000818:Animals; D019313:BRCA1 Protein / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019556:COS Cells / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019398:Genes, BRCA1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018167:Receptors, Calcitriol / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D019313:BRCA1 Protein; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D002117:Calcitriol