Document Detail

Point mutation of estrogen receptor (ER) in the ligand-binding domain changes the pharmacology of antiestrogens in ER-negative breast cancer cells stably expressing complementary DNAs for ER.
MedLine Citation:
PMID:  1491696     Owner:  NLM     Status:  MEDLINE    
The antiestrogen tamoxifen is used in the treatment of hormone-responsive breast cancer. However, therapeutic failure has frequently been observed in both patients and animal models after long term treatment. We have studied the effect of a point mutation that leads to the substitution of Val for Gly at codon 400 in the ligand-binding domain of the estrogen receptor (ER) on estrogenic and antiestrogenic activities of 4-hydroxytamoxifen (4-OHT) and its derivatives. Stable ER transfectants derived from MDA-MB-231 CL10A, an ER-negative breast cancer cell line, have been used in these studies. 4-OHT and its fixed ring derivatives showed more estrogen-like activity in ER transfectants than in MCF-7, an ER-positive breast cancer cell line. In this study, 4-OHT was a partial agonist of cell growth in the transfectant S30 cells, which express the wild-type ER. However, it was a full agonist in the mutant ER transfectant ML alpha 2H, which expressed ER with Val at codon 400. The increased estrogenic activity of 4-OHT in ML alpha 2H cells was not due to the preferential isomerization of trans 4-OHT to cis 4-OHT, since the nonisomerizable fixed ring trans 4-OHT was a partial agonist for cell growth in S30 cells and was a full agonist in ML alpha 2H cells. Transient transfection using a reporter plasmid containing an estrogen response element demonstrated that fixed ring trans 4-OHT had estrogenic activity in ML alpha 2H cells.(ABSTRACT TRUNCATED AT 250 WORDS)
S Y Jiang; S M Langan-Fahey; A L Stella; R McCague; V C Jordan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  6     ISSN:  0888-8809     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  1992 Dec 
Date Detail:
Created Date:  1993-02-26     Completed Date:  1993-02-26     Revised Date:  2013-05-27    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2167-74     Citation Subset:  IM    
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison 53792.
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MeSH Terms
Breast Neoplasms / pathology*
DNA / genetics
Estrogen Antagonists / pharmacology*
Mutagenesis, Site-Directed
Neoplasm Proteins / drug effects*,  genetics,  metabolism
Receptors, Estrogen / drug effects*,  genetics,  metabolism
Recombinant Fusion Proteins / drug effects*,  genetics,  metabolism
Structure-Activity Relationship
Tamoxifen / analogs & derivatives,  chemistry,  pharmacology
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Estrogen Antagonists; 0/Neoplasm Proteins; 0/Receptors, Estrogen; 0/Recombinant Fusion Proteins; 10540-29-1/Tamoxifen; 17197F0KYM/afimoxifene; 9007-49-2/DNA

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