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Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer

  1. Author:
    Wang, L. H.
    Yang, X. Y.
    Zhang, X. H.
    An, P.
    Kim, H. J.
    Huang, J. Q.
    Clarke, R.
    Osborne, C. K.
    Inman, J. K.
    Appella, E.
    Farrar, W. L.

  2. Author Address

    NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Canc Stem Cell Sect, Lab Canc Prevent, Frederick, MD 21702 USA. Georgetown Univ, Dept Oncol, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Methodist Hosp, Houston, TX 77030 USA. Baylor Coll Med, Breast Ctr, Houston, TX 77030 USA. NIAID, Bioorgan Chem Sect, Immunol Lab, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, Bethesda, MD 20892 USA.;Wang, LH, NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA.;lhwang@ncifcrf.gov farrar@ncifcrf.gov
    1. Year: 2006
    2. Date: Dec
  2. Journal: Cancer Cell
    1. 10
    2. 6
    3. Pages: 487-499
  4. Type of Article: Article
  5. ISSN: 1535-6108
  1. Abstract:

    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 ER alpha 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 ER alpha may induce a switch from agonistic to antagonistic effects of TAM on resistant breast cancer cells.

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External Sources

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  2. DOI: 10.1016/j.ccr.2006.09.015
  3. View record in Web of Science®
  4. WOS: 000242953000007

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