| Wilms' tumor 1 suppressor gene mediates antiestrogen resistance via down-regulation of estrogen receptor-alpha expression in breast cancer cells. | |
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MedLine Citation:
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PMID: 18708366 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The antiestrogen tamoxifen has been used in the treatment of hormone-responsive breast cancer for over a decade. The loss of estrogen receptor (ER) expression is the most common mechanism for de novo antiestrogen resistance. Wilms' tumor 1 suppressor gene (WT1) is a clinically useful marker that is associated with poor prognosis in breast cancer patients; its high level expression is frequently observed in cases of breast cancer that are estrogen and progesterone receptor negative. The lack of expression of these receptors is characteristic of tumor cells that are not responsive to hormonal manipulation. To determine whether there is a linkage between WT1 expression and antiestrogen resistance in breast cancer cells, we studied the effect of WT1 on tamoxifen responsiveness in ERalpha-positive MCF-7 cells. We found that overexpression of WT1 in MCF-7 markedly abrogated tamoxifen-induced cell apoptosis and 17beta-estradiol (E(2))-mediated cell proliferation. The expressions of ERalpha and its downstream target genes were significantly repressed following overexpression of WT1, whereas the down-regulation of WT1 by WT1 shRNA could enhance ERalpha expression and the sensitivity to tamoxifen treatment in ERalpha-negative MDA468 and HCC1954 cells that express high levels of WT1. Furthermore, we have confirmed that the WT1 protein can bind to endogenous WT1 consensus sites in the proximal promoter of ERalpha and thus inhibit the transcriptional activity of the ERalpha promoter in a WT1 site sequence-specific manner. Our study clearly implicates WT1 as a mediator of antiestrogen resistance in breast cancer through down-regulation of ERalpha expression and supports the development of WT1 inhibitors as a potential means of restoring antiestrogen responsiveness in breast cancer therapy. |
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Authors:
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Youqi Han; Lin Yang; Fernando Suarez-Saiz; Serban San-Marina; Jie Cui; Mark D Minden |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular cancer research : MCR Volume: 6 ISSN: 1541-7786 ISO Abbreviation: Mol. Cancer Res. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-08-18 Completed Date: 2008-09-26 Revised Date: 2011-04-21 |
Medline Journal Info:
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Nlm Unique ID: 101150042 Medline TA: Mol Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1347-55 Citation Subset: IM |
Affiliation:
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Princess Margaret Hospital/Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2M9. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Binding Sites Breast Neoplasms / genetics*, pathology Cell Line, Tumor Cell Proliferation / drug effects Consensus Sequence Down-Regulation / drug effects* Drug Resistance, Neoplasm / drug effects* Estradiol / pharmacology Estrogen Receptor Modulators / pharmacology* Estrogen Receptor alpha / genetics*, metabolism Gene Expression Regulation, Neoplastic / drug effects* Gene Silencing Genes, Neoplasm Mice Promoter Regions, Genetic / genetics RNA, Small Interfering / metabolism Tamoxifen / pharmacology Transcription, Genetic / drug effects Transfection WT1 Proteins / genetics* |
| Chemical | |
Reg. No./Substance:
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0/Estrogen Receptor Modulators; 0/Estrogen Receptor alpha; 0/RNA, Small Interfering; 0/WT1 Proteins; 0/estrogen receptor alpha, human; 10540-29-1/Tamoxifen; 50-28-2/Estradiol |
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