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Treatment
> Tamoxifen
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Cancer Cell. 2006 Dec;10(6):487-99; doi:10.1016/j.ccr.2006.09.015; Available
online 11 December 2006.
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Abstract |
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Disruption of estrogen receptor
DNA-binding domain and related intramolecular communication restores
tamoxifen sensitivity in resistant breast cancer
Li Hua Wang 1,
7, *, Xiao Yi Yang1,
7, Xiaohu Zhang1,
Ping An1, Han-Jong Kim2,
Jiaqiang Huang1, Robert Clarke3,
C. Kent Osborne4, John K. Inman5,
Ettore Appella6 and William L. Farrar2,
**
1Basic Research
Program, SAIC-Frederick, National Cancer Institute-Frederick,
Frederick, Maryland 21702. 2Cancer Stem Cell Section,
Laboratory of Cancer Prevention, National Cancer Institute-Frederick,
Frederick, Maryland 21702. 3Department of Oncology,
Lombardi Cancer Center, Georgetown University, Washington, District of
Columbia 20007. 4Breast Center, Baylor College of Medicine,
and The Methodist Hospital, One Baylor Plaza, BCM 600, Houston, Texas
77030. 5Bioorganic Chemistry Section, Laboratory of
Immunology, National Institute of Allergy and Infectious Diseases,
Bethesda, Maryland 20892. 6Laboratory of Cell Biology,
National Cancer Institute, Bethesda, Maryland 20892. -- 7These
authors contributed equally to this work. -- *Corresponding author,
Email: lhwang@ncifcrf.gov, **Corresponding author, Email:
farrar@ncifcrf.gov -- Received 18 December 2005; revised 8 April
2006; accepted 28 September 2006. Published: December 11,
2006. Available online 11 December 2006.
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A serious obstacle to successful treatment
of estrogen receptor (ER)-positive human breast cancer is cell
resistance to tamoxifen (TAM) therapy.
Here we show that the electrophile
disulfide benzamide (DIBA), an ER zinc finger inhibitor, blocks ligand-dependent
and -independent cell growth of TAM-resistant breast cancer in vitro
and in vivo.
Such inhibition depends on targeting
disruption of the ER DNA-binding domain and its communication with
neighboring functional domains, facilitating ERα dissociation
from its coactivator AIB1 and concomitant association with its
corepressor NCoR bound to chromatin.
DIBA does not affect phosphorylation of
HER2, MAPK, AKT, and AIB1, suggesting that DIBA-modified ERα may
induce a switch from agonistic to antagonistic effects of TAM on
resistant breast cancer cells.
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Copyright © 2006 Elsevier B.V.
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