A noncompetitive small molecule inhibitor of estrogen-regulated gene expression and breast cancer cell growth that enhances proteasome-dependent degradation of estrogen receptor {alpha}.
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.
Department of Biochemistry, University of Illinois, Urbana, Illinois 61801-3602, USA.
Nicole M
NM
Kretzer
Milu T
MT
Cherian
Chengjian
C
Mao
Irene O
IO
Aninye
Philip D
PD
Reynolds
Rachel
R
Schiff
Paul J
PJ
Hergenrother
Steven K
SK
Nordeen
Elizabeth M
EM
Wilson
David J
DJ
Shapiro
D001943:Breast Neoplasms / Q000378:metabolism*; D002090:Butyrophenones / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D005454:Fluorescence Polarization; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008956:Models, Chemical; D018396:Mucin-1 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
C555656:4-fluoro-4-(1,2,3,6-tetrahydro-1,3-dimethyl-2-oxo-6-thionpurin-8-ylthio)butyrophenone; D002090:Butyrophenones; D047628:Estrogen Receptor alpha; D007976:Leupeptins; D018396:Mucin-1; D011687:Purines; D012333:RNA, Messenger; D013629:Tamoxifen; C016601:afimoxifene; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde