Document Detail

Altered nuclear receptor corepressor expression attenuates vitamin D receptor signaling in breast cancer cells.
MedLine Citation:
PMID:  16609009     Owner:  NLM     Status:  MEDLINE    
PURPOSE: We hypothesized that deregulated corepressor actions, with associated histone deacetylation activity, epigenetically suppressed vitamin D receptor (VDR) responsiveness and drives resistance towards 1alpha,25-dihydroxyvitamin D(3).
EXPERIMENTAL DESIGN: Profiling, transcriptional, and proliferation assays were undertaken in 1alpha,25(OH)(2)D(3)-sensitive MCF-12A nonmalignant breast epithelial cells, a panel of breast cancer cell lines, and a cohort of primary breast cancer tumors (n = 21).
RESULTS: Elevated NCoR1 mRNA levels correlated with suppressed regulation of VDR target genes and the ability of cells to undergo arrest in G(1) of the cell cycle. A similar increased ratio of corepressor mRNA to VDR occurred in matched primary tumor and normal cells, noticeably in estrogen receptor alpha-negative (n = 7) tumors. 1alpha,25(OH)(2)D(3) resistance in cancer cell lines was targeted by cotreatments with either 1alpha,25(OH)(2)D(3) or a metabolically stable analogue (RO-26-2198) in combination with either trichostatin A (TSA; histone deacetylation inhibitor) or 5-aza-2'-deoxycytidine (DNA methyltransferase inhibitor). Combinations of vitamin D(3) compounds with TSA restored VDR antiproliferative signaling (target gene regulation, cell cycle arrest, and antiproliferative effects in liquid culture) to levels which were indistinguishable from MCF-12A cells.
CONCLUSIONS: Increased NCoR1 mRNA is a novel molecular lesion in breast cancer cells, which acts to suppress responsiveness of VDR target genes, resulting in 1alpha,25(OH)(2)D(3) resistance and seems to be particularly associated with estrogen receptor negativity. This lesion provides a novel molecular diagnostic and can be targeted by combinations of vitamin D(3) compounds and low doses of TSA.
Claire M Banwell; Donia P MacCartney; Michelle Guy; Alice E Miles; Milan R Uskokovic; Janine Mansi; Paul M Stewart; Laura P O'Neill; Bryan M Turner; Kay W Colston; Moray J Campbell
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  12     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-04-12     Completed Date:  2006-07-18     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2004-13     Citation Subset:  IM    
Institute of Biomedical Research, Endocrinology and Metabolism and Division of Immunity and Infection, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom.
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MeSH Terms
Azacitidine / analogs & derivatives,  pharmacology
Breast Neoplasms / metabolism*
Calcitriol / pharmacology
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cholecalciferol / analogs & derivatives,  pharmacology
Hydroxamic Acids / pharmacology
Nuclear Proteins / drug effects,  genetics*,  metabolism*
Nuclear Receptor Co-Repressor 1
RNA, Messenger / drug effects,  genetics
Receptors, Calcitriol / drug effects,  metabolism*
Repressor Proteins / drug effects,  genetics*,  metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction* / drug effects
Structure-Activity Relationship
Time Factors
Tumor Cells, Cultured
Reg. No./Substance:
0/1,25(OH)2-16-ene-23-yne-26,27-hexafluoro-19-nor-D3; 0/Hydroxamic Acids; 0/NCOR1 protein, human; 0/Nuclear Proteins; 0/Nuclear Receptor Co-Repressor 1; 0/RNA, Messenger; 0/Receptors, Calcitriol; 0/Repressor Proteins; 320-67-2/Azacitidine; 32222-06-3/Calcitriol; 3X2S926L3Z/trichostatin A; 67-97-0/Cholecalciferol; 776B62CQ27/decitabine

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