Linked Life Data

21041310

Source:http://linkedlifedata.com/resource/pubmed/id/21041310

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
53
pubmed:dateCreated
2010-12-27
pubmed:abstractText
The mechanisms responsible for 17?-estradiol (E(2))-stimulated breast cancer growth and development of resistance to tamoxifen and other estrogen receptor ? (ER?) antagonists are not fully understood. We describe a new tool for dissecting ER? action in breast cancer, p-fluoro-4-(1,2,3,6,-tetrahydro-1,3-dimethyl-2-oxo-6-thionpurin-8-ylthio) (TPSF), a potent small-molecule inhibitor of estrogen receptor ? that does not compete with estrogen for binding to ER?. TPSF noncompetitively inhibits estrogen-dependent ER?-mediated gene expression with little inhibition of transcriptional activity by NF-?B or the androgen or glucocorticoid receptor. TPSF inhibits E(2)-ER?-mediated induction of the proteinase inhibitor 9 gene, which is activated by ER? binding to estrogen response element DNA, and the cyclin D1 gene, which is induced by tethering ER? to other DNA-bound proteins. TPSF inhibits anchorage-dependent and anchorage-independent E(2)-ER?-stimulated growth of MCF-7 cells but does not inhibit growth of ER-negative MDA-MB-231 breast cancer cells. TPSF also inhibits ER?-dependent growth in three cellular models for tamoxifen resistance; that is, 4-hydroxytamoxifen-stimulated MCF7ER?HA cells that overexpress ER?, fully tamoxifen-resistant BT474 cells that have amplified HER-2 and AIB1, and partially tamoxifen-resistant ZR-75 cells. TPSF reduces ER? protein levels in MCF-7 cells and several other cell lines without altering ER? mRNA levels. The proteasome inhibitor MG132 abolished down-regulation of ER? by TPSF. Thus, TPSF affects receptor levels at least in part due to its ability to enhance proteasome-dependent degradation of ER?. TPSF represents a novel class of ER inhibitor with significant clinical potential.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
31
pubmed:volume
285
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
41863-73
pubmed:dateRevised
2011-2-14
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
A noncompetitive small molecule inhibitor of estrogen-regulated gene expression and breast cancer cell growth that enhances proteasome-dependent degradation of estrogen receptor {alpha}.
pubmed:affiliation
Department of Biochemistry, University of Illinois, Urbana, Illinois 61801-3602, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural