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A Noncompetitive Small Molecule Inhibitor of Estrogen-Regulated Gene Expression and Breast Cancer Cell Growth That Enhances Proteasome-Dependent Degradation of Estrogen Receptor {alpha}

A Noncompetitive Small Molecule Inhibitor of Estrogen-Regulated Gene Expression and Breast Cancer Cell Growth That Enhances Proteasome-Dependent Degradation of Estrogen Receptor {alpha}

Nicole M Kretzer, Milu T Cherian, Chengjian Mao, Irene O Aninye, Philip D Reynolds, Rachel Schiff, Paul J Hergenrother, Steven K Nordeen, Elizabeth M Wilson, David J Shapiro

J Biol Chem. 2010 Dec 31;285(53):41863-73.

PMID: 21041310

Abstract:

The mechanisms responsible for 17β-estradiol (E(2))-stimulated breast cancer growth and development of resistance to tamoxifen and other estrogen receptor α (ERα) antagonists are not fully understood. We describe a new tool for dissecting ERα 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 α that does not compete with estrogen for binding to ERα. TPSF noncompetitively inhibits estrogen-dependent ERα-mediated gene expression with little inhibition of transcriptional activity by NF-κB or the androgen or glucocorticoid receptor. TPSF inhibits E(2)-ERα-mediated induction of the proteinase inhibitor 9 gene, which is activated by ERα binding to estrogen response element DNA, and the cyclin D1 gene, which is induced by tethering ERα to other DNA-bound proteins. TPSF inhibits anchorage-dependent and anchorage-independent E(2)-ERα-stimulated growth of MCF-7 cells but does not inhibit growth of ER-negative MDA-MB-231 breast cancer cells. TPSF also inhibits ERα-dependent growth in three cellular models for tamoxifen resistance; that is, 4-hydroxytamoxifen-stimulated MCF7ERαHA cells that overexpress ERα, fully tamoxifen-resistant BT474 cells that have amplified HER-2 and AIB1, and partially tamoxifen-resistant ZR-75 cells. TPSF reduces ERα protein levels in MCF-7 cells and several other cell lines without altering ERα mRNA levels. The proteasome inhibitor MG132 abolished down-regulation of ERα by TPSF. Thus, TPSF affects receptor levels at least in part due to its ability to enhance proteasome-dependent degradation of ERα. TPSF represents a novel class of ER inhibitor with significant clinical potential.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP6505982	TPSF		6505-98-2	Price

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